Alzheimers Disease And Related Disorders Annual 5 Serge Gauthier

Alzheimers Disease And Related Disorders Annual 5 Serge Gauthier
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Alzheimers Disease And Related Disorders Annual 5 Serge Gauthier

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6. 5
ALZHEIMER’S
DISEASE AND
RELATED
DISORDERS
ANNUAL
00-Prelims (5) 8/31/05 11:00 AM Page i

7. 00-Prelims (5) 8/31/05 11:00 AM Page ii

8. 5
ALZHEIMER’S
DISEASE AND
RELATED
DISORDERS
ANNUAL
Edited by
Serge Gauthier,MD FRCPC
Professor and Director
Alzheimer’s Disease Research Unit
McGill Centre for Studies in Aging
Douglas Hospital
Verdun PQ
CANADA
Philip Scheltens, MD PhD
Department of Neurology / Alzheimer Center
Academisch Ziekenhuis
Vrije Universiteit
Amsterdam
The Netherlands
Jeffrey L Cummings, MD
Reed Neurological Research Center
University of California, Los Angeles
Los Angeles, CA
USA
00-Prelims (5) 8/31/05 11:00 AM Page iii

9. © 2006 Taylor & Francis, an imprint of the Taylor & Francis Group
First published in the United Kingdom in 2006 by Taylor & Francis, an imprint of the Taylor &
Francis Group, 2 Park Square, Milton Park, Abingdon, Oxon OX14 4RN
Tel.: [phone]
Fax.: [phone]
E-mail: [email protected]
Website: www.tandf.co.uk/medicine
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or
transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or
otherwise, without the prior permission of the publisher or in accordance with the provisions of
the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited
copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP.
Although every effort has been made to ensure that all owners of copyright material have been
acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or
editions any omissions brought to our attention.
Although every effort has been made to ensure that drug doses and other information are present-
ed accurately in this publication, the ultimate responsibility rests with the prescribing physician.
Neither the publishers nor the authors can be held responsible for errors or for any consequences
arising from the use of information contained herein. For detailed prescribing information or
instructions on the use of any product or procedure discussed herein, please consult the prescrib-
ing information or instructional material issued by the manufacturer.
A CIP record for this book is available from the British Library.
Library of Congress Cataloging-in-Publication Data
Data available on application
ISBN 1 84184 561 2
978 1 84184 561 6
Distributed in North and South America by
Taylor & Francis
2000 NW Corporate Blvd
Boca Raton, FL 33431, USA
Within Continental USA Distributed in the rest of the world by
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Composition by Creative
Printed and bound in Great Britain by TJ International Ltd, Padstow, Cornwall
00-Prelims (5) 8/31/05 11:00 AM Page iv

10. List of Contributors vii
1. Neuropathology of mild cognitive impairment 1
in the elderly
Steven T DeKosky, Milos D Ikonomovic, Ronald L Hamilton,
David A Bennett, and Elliot J Mufson
2.Cerebrospinal fluid markers for the diagnosis 17
of Alzheimer’s disease
Niki Schoonenboom, Harald Hampel, Philip Scheltens,
and Mony de Leon
3.Executive control function in ‘mild’ cognitive 35
impairment and Alzheimer’s disease
Donald R Royall
4.Glycosaminoglycan mimetics in Alzheimer’s disease 63
Francine Gervais, Denis Garceau, Paul S Aisen, and
Serge Gauthier
5. Immunotherapy for Alzheimer’s disease 73
David Wilkinson
6.Cholesterol, copper, and statin therapy in 89
Alzheimer’s disease
D Larry Sparks, Suzana Petanceska, Marwan Sabbagh,
Donald Connor, Holly Soares, Charles Adler, Jean Lopez,
Nina Silverberg, Kathryn Davis, Suhair Stipho-Majeed,
Sherry Johnson-Traver, Paul Volodarsky, Chuck Ziolkowski,
Jeff Lochhead, and Patrick Browne
v
Contents
00-Prelims (5) 8/31/05 11:00 AM Page v

11. 7.Insulin resistance in Alzheimer’s disease – 111
a novel therapeutic target
Suzanne Craft, Mark A Reger, and Laura D Baker
8. Atypical antipsychotics in dementia 135
Lesley M Blake and Jacobo Mintzer
9.Treatment of vascular risk factors to delay 153
Alzheimer’s disease?
Frank-Erik de Leeuw, Raj Kalaria, and Philip Scheltens
10.Cognitive dysfunction in multiple sclerosis 165
Julie A Bobholz and Angela Gleason
11.Cholinesterase inhibitors in the treatment of 181
dementia associated with Parkinson’s disease
Murat Emre
12.Modern applications of electroencephalography 191
in dementia diagnosis
CJ Stam
Index 207
00-Prelims (5) 8/31/05 11:00 AM Page vi

12. vii
Charles AdlerPhD
Mayo Clinic
Scottsdale, AZ
USA
Paul S AisenMD
Department of Neurology
Georgetown University Medical Center
Washington, DC
USA
Laura D BakerPhD
Assistant Professor of Psychiatry and
Behavioral Sciences, University of
Washington School of Medicine,
Geriatric Research, Education and
Clinical Center, Veterans Affairs Puget
Sound Health Care System
Seattle, WA
USA
David A BennettMD
Rush Alzheimer’s Disease Center
Rush university Medical Center
Chicago, IL
USA
Lesley M BlakeMD
Division of Geriatric Psychiatry
Northwestern University Medical
School
Chicago, IL
USA
Julie A BobholzPhD
Assistant Professor of Neurology
Medical College of Wisconsin
Milwaukee, WI
USA
Patrick Browne MD
Center for Chest Disease
Division of Cardiology
Boswell Hospital
Sun City, AZ
USA
Donald Connor PhD
Cleo Roberts Clinical Research Center
Sun Health Research Institute
Sun City, AZ
USA
Suzanne Craft PhD
Professor of Psychiatry and Behavioral
Sciences
University of Washington School of
Medicine
Associate Director,
Geriatric Research, Education and
Clinical Center
Veterans Affairs Puget Sound Health
Care System
Seattle, WA
USAContributors
00-Prelims (5) 8/31/05 11:00 AM Page vii

13. Jeffrey L CummingsMD
Department of Neurology
David Geffen School of Medicine at
UCLA
Los Angeles, CA
USA
Kathryn DavisBA
Sun Health Research Institute
Sun City, AZ
USA
Steven T DeKoskyMD
Department of Neurology
University of Pittsburgh School of
Medicine
Pittsburgh, PA
USA
FE De Leeuw MD PhD
Department of Neurology
University Medical Center St. Radboud
Nijmegen
The Netherlands
Mony de LeonPhD
New York University School of
Medicine
Center for Brain Health
New York, NY
USA
Murat EmreMD
Professor of Neurology
Head, Behavioral Neurology and
Movement Disorders Unit
Department of Neurology
Istanbul Faculty of Medicine
Çapa, Istanbul
Turkey
Denis GarceauPhD
Drug Development
Neurochem
Laval, Quebec
Canada
Serge Gauthier MD FRCPC
Professor and Director
Alzheimer’s Disease Research Unit
McGill Centre for Studies in Aging
Douglas Hospital
Verdun PQ
Canada
Francine GervaisPhD
Vice-President, R&D
Neurochem
Laval
Quebec
Canada
Angela Gleason PhD
Postdoctoral Fellow
Department of Neurology
Medical College of Wisconsin
Milwauke, WI
USA
Ronald L HamiltonMD
Division of Neuropathology
Department of Pathology
University of Pittsburgh School of
Medicine
Pittsburgh, PA
USA
Harald Hampel PhD
Department of Psychiatry
University of Munich
Nussbaumstr. 7
Munich
Germany
Milos D Ikonomovic MD
Alzheimer’s Disease Research Center
University of Pittsburgh School of
Medicine
Pittsburgh, PA
USA
viiiALZHEIMER’SDISEASE ANDRELATEDDISORDERSANNUAL
00-Prelims (5) 8/31/05 11:00 AM Page viii

14. Sherry Johnson-Traver
Sun Health Research Institute
Sun City, AZ
USA
Raj N KalariaMD
Wolfson Research Centre
Institute for Ageing and Health
Newcastle General Hospital
Westgate Road
Newcastle upon Tyne
UK
Jeff Lochhead BS
Sun Health Research Institute
Sun City, AZ
USA
Jean LopezRN MSN
Cleo Roberts Clinical Research Center
Sun Health Research Institute
Sun City, AZ
USA
Jacobo E MintzerMD
Medical University of South Carolina
Charleston, SC
USA
Elliot J MufsonPhD
Division of Neuroscience
Rush University
Rush Presbyterian St Luke’s Medical
Center
Chicago, IL
USA
Suzana PetanceskaPhD
Nathan Kline Institute and
Deptartments of Psychiatry and
Pharmmacology
New York University Medical Center
Orangeburg, NY
USA
Mark A RegerPhD
Acting Assistant Professor of Psychiatry
and Behavioral Sciences
University of Washington School of
Medicine
Geriatric Research, Education and
Clinical Center
Veterans Affairs Puget Sound Health
Care System
Seattle, WA
USA
Donald R Royall MD
Julia and Van Buren Parr Professor
for Alzheimer’s research in psychiatry
Chief: Geriatric Psychiatry Division
The University of Texas Health Sciences
Center at San Antonio
San Antonio, TX
USA
Marwan Sabbagh MD
Cleo Roberts Clinical Research Center
Sun Health Research Institute
Sun City, AZ
USA
Philip Scheltens MD PhD
Department of Neurology/Alzheimer
Center
VU University Medical Center
Amsterdam
The Netherlands
Niki Schoonenboom MD
Department of Neurology/Alzheimer
Center
VU University Medical Center
Amsterdam
The Netherlands
Nina Silverberg PhD
Sun Health Research Institute
Sun City, AZ
USA
CONTRIBUTORSix
00-Prelims (5) 8/31/05 11:00 AM Page ix

15. Holly SoaresPhD
Pfizer Global R&D
Groton, CT
USA
D Larry Sparks PhD
Ralph and Muriel Roberts Laboratory
for Neurodegenerative Disease Research
and
The Cleo Roberts Center for Clinical
Research
Sun Health Research Institute
Sun City, AZ
USA
Cornelis J StamMD PhD
Professor of Clinical Neurophysiology
Department of Clinical
Neurophysiology
VU University Medical Center
Amsterdam
The Netherlands
Suhair Stipho-MajeedMB ChB
CCRC
Sun Health Research Institute
Sun City, AZ
USA
Paul Volodarsky BS
Sun Health Research Institute
Sun City, AZ
USA
David WilkinsonMD
Consultant in Old Age Psychiatry and
Honorary Clinical Senior Lecturer
Memory Assessment and Research
Centre
Moorgreen Hospital
Botley Road
West End
Southampton
UK
Chuck ZiolkowskiBS
Sun Health Research Institute
Sun City, AZ
USA
xALZHEIMER’SDISEASE ANDRELATEDDISORDERSANNUAL
00-Prelims (5) 8/31/05 11:00 AM Page x

16. INTRODUCTION
The relationship of neuropathologic changes to the clinical status of people
with dementia is of paramount importance in devising appropriate therapeutic
interventions. Despite the fact that a central feature of the diagnostic criteria
for Alzheimer’s disease (AD) includes a history of insidious onset and a pro-
gression of cognitive decline, it was not until the mid 1990s, as large-scale
memory clinics obtained increased experience with people presenting early
with symptoms of mild dementia, that attention was directed at understanding
the processes occurring during the prodromal stages of dementia. Subse-
quently, individuals with mild memory loss, who were clinically followed
as their cognition deteriorated through stages of mild, moderate, and
severe AD, were neuropathologically confirmed postmortem as AD. These
neuropathologic findings, together with retrospective and prospective imaging
studies, led to a reexamination of our concepts of the neuropathologic changes
underlying the onset of early symptoms of cognitive impairment, as well as
the clinical definition of prodromal AD. Because it is believed that AD has an
extensive preclinical phase, it is important to identify people in an early stage
when brain pathology has been initiated but prior to significant clinical symp-
toms. During the past few years, the concept of mild cognitive impairment
(MCI) has developed as a possible prodromal stage of AD. Although the pre-
cise definition of MCI is being debated, recent evidence suggests that MCI falls
into several subtypes. Individuals with isolated memory loss, termed amnestic
mild cognitive impairment (aMCI), represent the most extensively analyzed
form of MCI in specialty clinics. The ‘conversion rate’ of aMCI people to AD
(the time at which they meet current formal criteria for AD) is 10–15% annu-
ally.
1
On the other hand, mild impairment defined by deficits in other cogni-
tive (and functional) domains is termed multiple domain MCI (mdMCI) and
may also occur as memory function declines below a defined threshold. In a
recent series of studies examining the onset of MCI in the Cardiovascular
Health Study (CHS) cohort, the risk factors for developing MCI included
apoE4 genotype (for aMCI), depression, racial and constitutional factors, and
1
1
Neuropathology of mild cognitive
impairment in the elderly
Steven T DeKosky, Milos D Ikonomovic, Ronald L Hamilton, David A Bennett, and Elliot J Mufson
01-Chapter 1 5 8/31/05 11:04 AM Page 1

17. the presence of cerebrovascular disease.
2
In this population-based study, about
two-thirds of the MCI cases were mdMCI, and about one-third were aMCI.
3
Thus, a MCI is not as common in population-studies, and may be a less
frequent manner of progressing to AD. This chapter provides an overview of
neurobiologic observations crucial to our understanding of the chemical,
pathologic, and molecular changes which occur in brain during the transition-
al period between normal aging and the clinical diagnosis of all forms of MCI
and AD.
CLINICAL PRESENTATION OF MILD COGNITIVE
IMPAIRMENT
Clinical and neuropathologic data necessary for the investigation of MCI have
been derived from two types of cohorts. First are large clinic populations,
which have (small numbers of) subjects who come to autopsy while still clini-
cally classified as MCI. For example, the Alzheimer Disease Center at
Washington University, St Louis, have reported autopsy results from their
cohort of cases, some of whom died with a Clinical Dementia Rating (CDR) of
0.5, indicative of MCI.
4,5
A second source are volunteer cohorts of individuals
in a population study, such as the Nun Study
6
and the Religious Orders Study
(ROS),
7,8
in which all subjects agree to yearly cognitive and neurologic exami-
nation and brain autopsy at time of death. Because of their large size and
advanced age of their subjects, these cohorts enable the assessment of the
extent of pathologic and neurochemical changes in the brain associated with
cognitive changes in particular diagnostic categories, including normal cogni-
tion, MCI, and mild, moderate, and severe AD. In all of these cohorts MCI
marked a transitional state, with a decline of cognitive function that exceeded
the norms for the respective populations. However, the definitions of MCI
were somewhat different across cohorts. For example, a 0.5 CDR is used by
several groups as an indicator of MCI, whereas the ROS uses an actuarial deci-
sion tree that incorporates and can be overridden by clinical judgment, and
the Nun Study employs neuropsychologic testing patterns. Thus, the clinical
definition or diagnosis of MCI remains variable and perhaps controversial. In
this regard, Washington University utilized the CDR scale
9,10
to determine the
presence or absence of MCI (CDR 0.5) and referred to them either as very
mild AD or ‘early stage AD’.
11
Because the CDR 0.5 represents a global cogni-
tive score, these studies were careful in characterizing the specific cognitive
domains that can be affected in MCI subjects, segregating them further into
groups where cognitive impairment is uncertain (CDR 0.5/uncertain demen-
tia), or detected selectively in the memory domain (CDR 0.5), in memory and
up to two other domains (CDR 0.5/incipient dementia of the Alzheimer’s type,
DAT), or in memory and no less than 3 CDR domains (CDR 0.5/DAT).
11
Less
confident diagnosis of MCI was categorized as CDR 0/0.5, which proved not
to be distinct neuropathologically from CDR 0.5.
5,12
The CDR 0.5 cases are
2ALZHEIMER’SDISEASE ANDRELATEDDISORDERSANNUAL
01-Chapter 1 5 8/31/05 11:04 AM Page 2

18. comparable to MCI subjects from the ROS cohort or to ‘mild impairment –
memory impaired’ subjects from the Nun Study.
6
Clinical evaluation of the ROS population relied on a battery of tests that
included MMSE (Mini-Mental State Examination) as a measure of global cog-
nitive function,
13
seven tests of episodic memory, and 13 tests of other cogni-
tive abilities (for details of the cognitive function tests in ROS, see Wilson et
al
14
). Based on these tests, MCI subjects in the ROS were classified into aMCI
with impaired episodic memory and non-amnestic MCI without episodic
memory impairment.
15
In the Nun Study, MCI were defined as subjects with-
out dementia, who had preserved global cognition (measured by MMSE) and
normal daily activities, but who were impaired in either memory or another
cognitive domain.
6
However, the authors recognized that their MCI subjects
represented a mixed group of individuals impaired in multiple areas of cogni-
tion, or domains other than memory, whereas only a small proportion of them
were impaired in the isolated memory domain.
6
Similarly, many MCI cases in
the ROS studies are most likely also mdMCI, with impairment in one or more
cognitive areas.
Amyloid plaque pathology in MCI
The neuropathology of MCI is now being investigated in large-scale studies.
Studies from Washington University in St Louis have provided evidence that
virtually all subjects with a CDR score of 0.5 (approximately equivalent to
aMCI) displayed sufficient numbers of amyloid beta (Aβ) plaques and
neurofibrillary tangles (NFTs) to meet neuropathologic criteria for AD at
autopsy.
11
Using Khachaturian pathologic criteria,
16
only 1 in 8 of those cases
with no evidence of cognitive problems (CDR = 0 at entry and at death)
showed neuropathologic evidence of AD. While this suggests that many MCI
cases are preclinical AD, it did not define the extent of pathologic changes at
the time the person was first diagnosed with MCI. Recent clinical pathologic
investigations
17,18
provided evidence that 60% of MCI cases met the neu-
ropathologic diagnosis of AD according to CERAD
19
and NIA-Reagan
20
crite-
ria. Similarly, Petersen and colleagues reported that most of their MCI cases
postmortem displayed significant neuropathologic changes similar to AD.
1
Given that AD (and MCI) are being diagnosed earlier and earlier in the pro-
gression of dementia, perhaps it is time to rethink whether the amounts of
pathology needed to characterize a case as pathologic AD should be lower
than allowed by the current diagnostic standards.
Despite the fact that Aβplaques symbolize one of the major neuropathologic
hallmarks of AD, their role in the initiation of AD dementia remains unclear.
Neuropathologic studies of cognitively normal elderly have found that some
already have considerable Aβdeposition in the brain.
5,21
More importantly,
virtually all patients with MCI have Aβplaques.
5,22–24
Because Aβdeposition
is an early event in the course of AD, leading to other pathologies
(e.g. synapse loss, neuronal degeneration, and NFT formation) which corre-
late more closely with cognitive decline,
25,26
it becomes increasingly important
NEUROPATHOLOGY OFMCI IN THEELDERLY3
01-Chapter 1 5 8/31/05 11:04 AM Page 3

19. to define the extent of Aβpathology during clinical changes from cognitively
intact to MCI to AD.
Postmortem analysis of subjects in the St Louis community cohort found
significant numbers of Aβplaques in hippocampal and neocortical regions in
both CDR 0.5 and CDR 0/0.5 subjects.
27,28
The CDR 0.5 are not easily
distinguished from CDR 0/0.5 (questionable dementia), and were variably
considered as MCI or ‘early stage AD’ or ‘very mild dementia’.
11,27
The scarce
pathology in cognitively normal (CDR 0) individuals, reported in these and
other studies, indicates that brains of healthy aged people are, in general,
spared from Aβpathology and should be discriminated from ‘pathologic
aging’.
29
The CDR 0.5 cases had substantial and widespread Aβplaques in the
neocortex and to a lesser extent in the hippocampus, with a preponderance of
the diffuse type in the neocortex, and of neuritic types in the limbic regions
5
.
The pattern of Aβplaque pathology across subjects with CDR 0 and CDR 0.5
led Price and colleagues to propose a continuum of Aβplaque type that
changes during the conversion from normal (scarce diffuse plaques) to patho-
logic aging and MCI or ‘very mild dementia’ (many diffuse and neuritic
plaques).
12
The two clinical groups were different, based on densities of dif-
fuse and neuritic Aβplaques in the entorhinal cortex (ERC) and temporal
neocortex,
22
supporting the theory that Aβplaques may be of diagnostic value
in MCI.
4,30
The observations of extensive Aβplaque pathology in MCI had been con-
firmed in other cohorts. The Baltimore Longitudinal Study of Aging
31
included
two subjects with questionable dementia (CDR 0.5) who had moderate neurit-
ic plaque frequencies, and were assigned neuropathologic diagnoses of proba-
ble AD. A clinical pathologic investigation of cases from the Jewish Home and
Hospital in New York revealed that, compared with subjects with CDR 0, the
CDR 0.5 subjects with questionable dementia had significantly increased den-
sities of neuritic plaques in frontal, temporal, and parietal cortex, but not in
occipital cortex, ERC, hippocampus, and amygdala.
23
These data further sug-
gest that an increase in neocortical Aβpathology parallels the earliest sign of
cognitive decline in AD. An immunohistochemical study of Aβload in the
ERC from ROS subjects clinically diagnosed as MCI, not cognitively impaired
(NCI), or mild to moderate AD found that the MCI cases were intermediate
between the other two groups, with wide overlap and no statistically signifi-
cant difference.
24
Aβplaques were found in 83% of MCI, and the highest Aβ
load measured in this study was in an MCI case with a neuropathologic diag-
nosis of possible AD. The wide range of Aβcontent in subjects with MCI, and
the considerable overlap with cognitively normal and demented subjects, fur-
ther supported the suggestion of MCI as a transitional stage from normal aging
to AD. Furthermore, this indicates that some MCI subjects resist deteriorating
into dementia despite a considerable amount of plaque pathology in their
mesial temporal lobe. Alternatively, it is possible that the addition of plaque
pathology in other brain regions is more relevant for the clinical manifestation
of dementia.
4ALZHEIMER’SDISEASE ANDRELATEDDISORDERSANNUAL
01-Chapter 1 5 8/31/05 11:04 AM Page 4

20. Biochemical measurements of Aβ
40
and Aβ
42
Neocortical tissue obtained postmortem from subjects selected from the
Jewish Home and Hospital in New York was examined for soluble and insolu-
ble Aβ
40
and Aβ
42
levels and revealed significant variability of total amyloid
levels across CDR groups.
32
Compared to normal (CDR 0) controls, the CDR
0.5 subjects (questionable dementia) showed elevated levels of both Aβ
species in the ERC, frontal, parietal, and visual cortex, similar to the
Washington University findings of increased Aβplaques in their CDR 0.5
cases, although curiously not in the temporal lobe. Elevation of both Aβ
40
and
Aβ
42
levels correlated with the advancement of dementia. The authors con-
cluded that elevations in Aβlevels occurred very early in the disease progres-
sion, and this increase might influence the development of other types of AD
pathology.
In cerebrospinal fluid (CSF) samples and magnetic resonance imaging
(MRI) measurements taken from MCI and normal aged control subjects at
baseline and 1 year later, deLeon and colleagues combined ventricular volume
increases with measures of Aβas well as phosphorylated tau (pTau231).
33
Cross-sectionally, Aβ
40
but not Aβ
42
was increased, as was pTau231. One year
later, the only significant change was an increase in pTau231, and that
was only if the ventricular enlargement (implying greater CSF volume) was
considered in the calculations.
Tau/neurofibrillary pathology in MCI
Unlike Aβplaques, which may not be present in the brains of some of the very
elderly,
4
NFTs are an expected finding in all aged brains, although they may be
few in number and restricted to the ERC or hippocampus.
34–38
Considerable
amounts of pathologic tau (hyperphosphorylated tau aggregated into NFTs
and neuropil threads) have been reported in MCI. Price and colleagues
4,5
showed that ‘very mildly demented’/MCI cases (CDR 0/0.5 or 0.5) displayed
increased numbers of NFTs, particularly in the ERC and perirhinal cortex,
when compared with cognitively normal (CDR 0) controls. However, CDR 0
controls often display NFTs in the medial temporal structures. Whereas a sub-
group of these NFT-positive CDR 0 cases lacked Aβdeposits, in CDR 0.5 cases
NFTs were always accompanied by Aβplaques, with the plaques being more
abundant in neocortical areas.
5
It was suggested that the initial NFT pathology
can occur without the presence of Aβplaques; however, advanced NFT densi-
ties are most likely to occur following Aβplaque formation.
5
In a review of
their cases, Morris and Price
30
noted that NFT distribution in these very mild
cases had not extended beyond the mesial temporal lobe, and suggested that
the presence of diffuse Aβplaques in the cortex marked the onset of AD.
Examination of subjects from the Baltimore Longitudinal Study of Aging
found that CDR 0.5 cases manifested NFTs in the hippocampus and amygdala,
only scarce numbers of NFTs were seen in ERC or inferior parietal cortex,
NEUROPATHOLOGY OFMCI IN THEELDERLY5
01-Chapter 1 5 8/31/05 11:04 AM Page 5

21. whereas other neocortical regions lacked NFTs.
31
Similar findings were report-
ed for CDR 0 controls in this study, consistent with observations by Price and
colleagues.
5
These observations suggest that, unlike Aβplaques, NFTs are less
likely to aid the distinction between normal aging and MCI. However, there is
a dramatic increase in entorhinal/hippocampal NFTs in the CDR 0.5 compared
to CDR 0.
28
Clinical pathologic investigations of subjects derived from the Jewish Home
and Hospital in New York revealed a significant positive correlation between
NFT densities and CDR scores.
37
However, NFT density in the CDR 0.5 sub-
jects with ‘questionable dementia’ was not different from CDR 0 controls; both
groups had NFTs in the ERC and hippocampus. This study suggested that
NFT pathology increased with progression of dementia severity, but it was not
a reliable pathologic marker to distinguish MCI. Similarly, a study of
“oldest-old” subjects autopsied in the Geriatric Hospital of the University of
Geneva in Switzerland showed that Braak neuropathologic staging
39
correlated
highly with clinical CDR scores. However, it was difficult to distinguish
between CDR 0 and CDR 0.5 groups in this cohort.
38
In the ROS population, the status of tau pathology was examined in MCI
(MMSE 26.8 ± 2, not different from controls), mild to moderate AD, and aged
control cases.
40
This study reported correlation of granulovacuolar and fibril-
lar lesions with several measures of episodic memory. Neuropil threads (NT)
preceded the appearance of NFT, which in turn appeared prior to neuritic Aβ
plaques. There were no statistically significant correlations between tau
pathology measurements and clinical classifications of NCI, MCI, and AD. A
quantitative stereologic investigation of phosphorylated tau pathology in the
parahippocampal gyrus from MCI, NCI, and AD subjects from the ROS cohort
demonstrated that MCI (MMSE 25.8 ± 2.9, not different from NCI) had a non-
significant increase in both NFT and NT densities compared to NCI.
41
In
contrast, the AD subjects showed significantly increased NFTs compared to
controls, but not MCI, and were comparable to controls with respect to NT
pathology.
41
Increasing NFT (but not NT) pathology correlated with impaired
performance on a measurement of episodic memory, suggesting that NFT
pathology plays a role in the clinical progression from NCI to MCI, and fur-
ther into AD. DeKosky and colleagues examined the relationship between the
extent of neuropathologic changes by NIA/Reagan criteria
18
or Braak stage
42
and choline acetyltransferase (ChAT) activity levels in ROS subjects. Almost
half of the MCI group had intermediate likelihood (NIA/Reagan category) of
AD, with another 11% having high likelihood;
18
53% of persons with MCI
were Braak stage III/IV and 18% were Braak stage V/VI.
42
These observations
of significant AD pathology in MCI were confirmed in an enlarged cohort of
MCI subjects from the same ROS cohort.
8
Further support for the hypothesis that NFT pathology influences MCI is
derived from a clinical pathologic evaluation of brain tissue harvested from the
Nun Study. This study reported a strong correlation between the progression
of NFT pathology, as defined by Braak staging, and cognitive impairment,
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22. especially in the younger age groups.
6
About half of MCI subjects (with intact
or impaired memory) were Braak stage I/II. This investigation pointed out the
variability of neuropathologic findings in mildly impaired people with or with-
out memory problems, at different stages of cognitive impairment at time of
death. After separating their MCI cases into a group with significant memory
impairment and those without much memory impairment, it was found that
23% of the non-memory impaired had Braak scores of 0 (no entorhinal NFTs).
On the other hand, in the memory impaired group, which is most comparable
to MCI in the literature, no cases lacked NFTs in the entorhinal/transento-
rhinal area.
An investigation of participants in a longitudinal study at the University of
Miami found that MCI patients (diagnosed as a selective impairment of mem-
ory function) showed considerably greater density of NFTs in the fusiform
gyrus and medial temporal areas compared with non-demented controls, while
Aβplaques were variable.
43
Additional studies of the quantitative changes in
tau pathology are needed to clarify whether this or other types of pathology
play a role in the clinical symptoms of MCI. Definition of MCI needs to be
carefully characterized in all such studies.
Neuronal cell pathology in MCI
Several studies have examined changes in neuronal numbers in MCI, focusing
either on the mesial temporal cortex or the cholinergic basal forebrain nuclei
(CBFN). The ERC, the major paralimbic cortical relay region for the transmis-
sion of cortical information to the hippocampus, was of interest because it
undergoes neurodegenerative changes in the earliest stages of disease progres-
sion.
28,39,44–47
Cases from the Washington University cohort showed no signif-
icant decrease in numbers of Nissl-stained neurons or ERC volume with age
in healthy non-demented individuals. Few or no differences were observed
between the healthy controls and what was termed ‘preclinical AD’, or cases
with normal cognition (CDR 0) but a good deal of accumulated plaques and
tangles at autopsy.
12
However, neuronal numbers were significantly decreased
in the ERC (35%; 50% of cells in lamina II) and hippocampal CA1 (46% loss)
in very mild AD (CDR 0/0.5 or CDR 0.5); cell loss was even more profound in
severe AD. These findings suggest that cell atrophy and death have already
occurred at a time when patients begin to manifest clinical symptoms of AD.
The results of these studies are consistent with a previous report by Gomez-
Isla and colleagues using cases from Washington University, which showed
similar neuronal loss in the ERC (32%; 57% in lamina II).
28
Unbiased quanti-
tative stereology revealed significant loss of NeuN-immunoreactive neurons in
the ERC lamina II of MCI (63%) and mild to moderate AD (58%) in cases
derived from the ROS cohort.
47
Moreover, there was also a reduction in lamina
II ERC volume in MCI (26%) and AD (43%), in agreement with previous find-
ings.
12
ERC atrophy correlated with impairment on MMSE and clinical tests of
declarative memory.
30,47
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23. Cholinergic basal forebrain system dysfunction
The cholinotrophic phenotype of the CBFN neurons is altered during the pro-
dromal and earliest stages of AD. Quantitative stereologic studies revealed that
the number of nucleus basalis (NB) perikarya expressing either ChAT, the syn-
thetic enzyme for acetylcholine, or the vesicular acetylcholine transporter
(VAChT) was stable in MCI and mild AD.
48
Moreover, other studies demon-
strated that ChAT activity in NB cortical projection sites is unchanged in mild
AD.
17,18
Taken together, these observations suggest that the enzymes underly-
ing basocortical cholinergic neurotransmission are preserved in MCI and early
AD, although cholinergic function is probably impaired as these neurons con-
tain NFTs.
49
The number of NB perikarya expressing either the high-affinity
nerve growth factor (NGF)-selective receptor trkA or the pan-neurotrophin
receptor p75
NTR
was reduced ~50% in MCI and mild AD compared with NCI,
and this deficit correlated significantly with impaired performance on the
MMSE and a few individual tests of working memory and attention.
50,51
Many
cholinergic NB neurons appear to undergo a phenotypic silencing of NGF
receptor expression in the absence of frank neuronal loss during the early
stages of cognitive decline, as trkA (but not p75
NTR
mRNA) was reduced in
NB neurons in MCI and AD
52
as well as in the cortex.
53
These alterations may
signify an early deficit in neurotrophic support during the progression of AD:
perhaps this related to the early declines in cholinergic function and the
sensitivity of the cholinergic system to cholinergic blockers.
54
NGF levels are preserved in the hippocampus and neocortex in MCI sub-
jects.
55
ProNGF (the precursor molecule for NGF) is elevated 1.4 times above
controls in the parietal cortex in MCI, and 1.6 times above control levels in
mild AD.
56
Thus, the perturbations in NGF signaling within the cholinotroph-
ic basal forebrain system in early AD may be initiated by defective NGF retro-
grade transport due to reduced receptor protein levels in cortical projection
sites, which ultimately affects NB neuronal survival, or due to alteration in the
ratio of cortical proNGF to trkA.
53
The presence of cell cycle proteins within
NB neurons in MCI and mild AD cases from the ROS cohort
57
suggests that
cortical NGF receptor imbalance may contribute to the selective vulnerability
of cholinergic NB neurons via deficits in trkA-mediated pro-survival signaling
and/or alterations in p75
NTR
-mediated signaling, which promotes unscheduled
cell cycle re-entry and apoptosis during the prodromal stages of AD.
Collectively, these data support the concept that MCI is associated with phe-
notypic changes (e.g. trkA, p75
NTR
), but not frank neuronal degeneration, in
the CBFN. Factors other than these particular markers of cholinergic neurons,
or dysfunction of other cell populations (e.g. ERC lamina II neurons), also
play a role in the differences in cognitive function.
Cholinergic enzyme changes in MCI
ChAT loss has been regarded as the hallmark neurotransmitter change in AD.
Most investigators have always presumed that loss of cholinergic function
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24. underlies much of the short-term memory loss in AD, and probably in MCI as
well. The observations that physostigmine and oral anticholinesterases have
beneficial effects for patients with AD suggest that the cholinergic basal fore-
brain system is altered despite the absence of ChAT enzyme deficits in AD. In
fact, a series of studies have shown that neocortical ChAT activity is preserved
in MCI.
17,18,58,59
Thus, cholinergic enzyme deficits are probably not the pri-
mary cause of the memory loss in MCI, although these studies do not rule out
other types of cholinergic dysfunction early in the disease course. On the
other hand, DeKosky and colleagues found elevated ChAT activity in the hip-
pocampus and frontal cortex of subjects with MCI.
18
These results suggested
that cognitive deficits in MCI and early AD are not associated with ChAT
reduction in the hippocampus, and that select components of the hippocam-
pal and cortical cholinergic projection system are capable of compensatory
responses during the early stages of dementia. Increased hippocampal and
frontal cortex ChAT activity in MCI may be important in promoting biochemi-
cal stability, or compensating for neurodegenerative defects, which may delay
the transition of these subjects to AD. Interestingly, hippocampal ChAT activi-
ty was increased selectively in those MCI cases scored as a Braak III/IV stage,
suggesting that a compensatory up-regulation of ChAT occurs during the pro-
gression of entorhinal–hippocampal NFT pathology.
42
This cholinergic up-
regulation is reminiscent of the cholinergic axonal plasticity response in the
hippocampus following denervation or loss of excitatory input from the ERC
lamina II neurons observed in animal models of AD
60
as well as in AD
brains.
61,62
This neuronal reorganization may account for the increase in ChAT
activity observed in the MCI hippocampus, considering the fact that NFT
changes involved most of the ERC lamina II neurons by the time these
subjects developed MCI.
18,42
The reasons for the elevation of ChAT in frontal
cortex in MCI is less clear, but is most probably also the result of cholinergic
sprouting.
Acetylcholinesterase (AChE), the enzyme that hydrolyzes acetylcholine at
the synapse, did not show decline in cortical areas until at least moderately
severe levels of dementia were present.
17
Positron emission tomography (PET)
studies, utilizing a ligand that labels AChE in vivo, suggested that there is only
mild loss of AChE in MCI
63
and mild AD.
64
Notably, in the latter study the
loss in AD was less than that in Parkinson’s disease or Parkinson’s dementia.
The manner in which this cholinergic enzyme impacts cognitive decline in AD
remains an area of great interest. Studies utilizing AChE PET ligands in large
sample sizes can be expected to be undertaken in the future.
Other neurochemical markers
Levels of isoprostane, 8,12-iso-iPF2alpha-VI, a sensitive marker for in-vivo
lipid peroxidation (and thus of degree of oxidative stress), are elevated in
urine, blood, and CSF in AD, and correlate with cognitive and functional
scores as well as CSF tau and amyloid concentrations.
65
To the extent that the
MCI cases had an intermediate level of the isoprostane, this study may
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25. indicate the degree of oxidative stress in the pathologic processes in MCI
brains. If confirmed, this method might have promise for diagnosis and as a
biomarker for the level of oxidative stress in AD.
Soluble alpha-synuclein (α-syn), a heat-stable protein that plays an impor-
tant role in neuronal plasticity, was significantly reduced in the frontal cortex
in AD patients compared with MCI and NCI patients from the ROS cohort;
there were no differences between MCI and NCI.
66
The immunoreactivity of
α-syn correlated with MMSE score and a global neuropsychologic z-score.
Similar results were found in a study examining the relation of Lewy bodies
identified with α-syn antibodies in the substantia nigra, limbic system, and
several neocortical regions in cases from the ROS.
8
About 10% of patients with
MCI and those without cognitive impairment had Lewy bodies; by contrast,
more than 20% of patients with dementia had Lewy bodies.
Both MCI and AD groups had markedly elevated expression of heme oxyge-
nase-1 (HO-1, an indirect marker of oxidative stress) in the hippocampus and
temporal neocortex.
67
Astroglial HO-1 immunoreactivity in the temporal cor-
tex, but not hippocampus, correlated with the burden of neurofibrillary
pathology. These data strengthen earlier observations suggesting that oxidative
stress may be a very early event in the pathogenesis of AD.
Synapse counts in MCI
Evaluation of synapse numbers in biopsy-derived
68
and postmortem
69
tissue
show a high correlation with cognitive impairment. Although there are no
published studies on the status of synaptic integrity in MCI, a preliminary
stereologic analysis of synapse counts in the hippocampus from ROS cases
showed remarkable variability.
70
In MCI, the number of synapses in two
regions of the hippocampus (CA1 and outer molecular layer of dentate gyrus)
was reduced on average, and the synaptic densities seemed to fall either in the
AD range or in the range of the controls. More cases will be needed to deter-
mine the precise nature of synapse loss in different regions of brain during the
progression of AD.
Subcortical (white matter) changes and cerebrovascular
disease
Subcortical white matter alterations and loss (subcortical atrophy leading to
hydrocephalus ex vacuo) are well-known correlates of AD. Thus, age-related
white matter changes, such as ubiquitin-immunoreactive granular degenera-
tion of myelin, may occur during the progression of AD and contribute to
cognitive (and motor) dysfunction. In an immunohistochemical study of ubiq-
uitin and myelin basic protein (MBP) in frontal white matter of subjects from
the ROS cohort, MBP was significantly decreased (28%) in mild AD but not in
MCI compared with control brain white matter samples.
71
MBP changes corre-
lated with both global and frontal function-specific tests of cognition, suggest-
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26. ing that white matter pathology may contribute to age- and disease-associated
cognitive decline.
An examination of the relationship of macroscopic cerebral infarctions to
MCI in ROS demonstrated that one-third of MCI cases had cerebral infarc-
tions.
8
This was in contrast to nearly 50% of patients with dementia and less
than 25% of patients without cognitive impairment.
CONCLUSIONS
Neuropathologic and neurochemical studies are emerging to aid in the defini-
tion of the brain’s status during the earliest stages of symptomatic cognitive
impairment as well as presymptomatic AD. Initial conclusions suggest that
significant Aβdeposition, NFT formation, and neuronal cell loss (especially in
the mesial temporal lobe), and alterations in the NGF neurotrophin receptor
system, are evident, but without major differences between cases with a clini-
cal diagnosis of MCI at death and those clinically diagnosed as ‘mild’ AD.
Other significant markers, or system disruptions, are yet to be identified. In
addition, the synaptic and cholinergic plasticity, which may differ from indi-
vidual to individual, no doubt contribute to the variability of the pathologic
findings. Based upon the multiple markers thus far explored, variability in the
MCI cases is going to be multidimensional, and there is no indication that one
specific pathologic or biochemical variable will be an absolute quantitative
marker of MCI.
It does not appear possible to predict accurately the extent/severity of neuro-
pathologic changes based only on the cognitive status of an individual. In cog-
nitively normal cases with only small numbers of NFTs in the ERC and few or
no Aβdeposits anywhere, one cannot accept these as being AD or even incipi-
ent AD. However, we can, to some degree, feel confident that nearly all cases
with some cognitive impairment (even MCI) will show pathologic changes
with varying degrees of NFTs and Aβplaques. MCI cases have a range of AD
pathology that includes NFTs in the ERC and Aβdeposits in the neocortex,
and show considerable overlap with the pathology found in ‘early AD’ to such
an extent that it is still impossible in a given case to accurately predict the
severity of clinical impairment based on the neuropathologic changes when
they are in low Braak stages (≤stage III) and contain less than a moderate
number of neuritic plaques in the neocortex.
There are several possible reasons for inconsistencies in the literature
describing the neuropathology of MCI, including insufficient sample size,
neuropathologic heterogeneity within and across diagnostic groups, selection
of the measure of pathologic changes, lack of a unified clinical definition of
MCI, and the possibility that the cognitive status at the time of death may
have progressed from the one that was determined during the last neuropsy-
chologic testing which served to establish the ‘final’ clinical diagnosis of MCI.
Thus, the antemortem interval from the last clinical diagnosis to death needs
NEUROPATHOLOGY OFMCI IN THEELDERLY11
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27. to be as short as possible. In most of the studies presented in this chapter, the
last clinical evaluation was performed within 1 year of death. A unified clinical
diagnostic and neuropathologic testing procedure, which would serve for
more consistent correlative investigations of cognitive status vs neuropatho-
logic changes, would also be of immense benefit for MCI research. For a vari-
ety of logistical reasons, that is not likely to happen. However, agreement
among groups which use different approaches would be powerful. The neu-
ropathologic distinction between MCI and cognitively normal aged people, or
those with early dementia, has also been difficult because a wide range of neuro-
pathologic changes were present in each of these clinical diagnostic groups,
with significant overlap. Brains of cognitively normal people often contain
substantial amounts of neuropathologic changes, including Aβplaques and
NFTs,
24,72,73
similar to what is seen in MCI. Studies relying on quantitative
biochemical measurements or direct (stereological) counting of neuropatho-
logic changes might be of help in improving the clinical/pathologic correlates.
The search for the status of the brain in MCI will continue with postmortem
analyses as well as in-vivo studies. Recent results indicate that Aβimaging in
vivo can be accomplished in AD.
74
Preliminary data on cases with MCI sug-
gest that, like the synapse data, the means of Aβload are midway between AD
cases and controls, but that the individual cases lie either in the range of nor-
mals or in the range of AD cases. On the other hand, recent MRI studies indi-
cate that MCI have reduced ERC and hippocampal volume
75,76
and higher rate
of hippocampal volume loss.
77
It is unlikely that a single marker, neuropatho-
logic or clinical, will emerge as a standard measure of MCI-specific pathology.
However, since there is great neuropathology overlap between MCI and AD,
the current data suggest that MCI is a prodromal form of AD.
ACKNOWLEDGMENTS
This work was supported by the NIA grants AG05133, AG14449, AG16668,
AG09446 and AG10161.
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32. INTRODUCTION
Alzheimer’s disease (AD) is considered to be the most common type of demen-
tia.
1
Due to the aging of the population, the number of persons affected by AD
is expected to increase three-fold by 2050.
2
The diagnosis of AD is made by exclusion and based on clinical criteria,
3
supported by neuropsychologic tests, neuroimaging, and extended follow-up.
In the early stage, it is difficult to differentiate AD from other types of demen-
tia, as the clinical symptoms are subtle and the diagnostic methods may be
normal. Furthermore, clinical overlap exists between the different types of
dementias, while volume changes of the hippocampus and medial temporal
lobe on magnetic resonance imaging (MRI) are not specific for AD.
4
With the
advent of novel therapeutic strategies,
5
it became important to diagnose AD as
early as possible, as pharmacologic treatment needs to be started before exten-
sive and irreversible brain damage has occurred. Over the last decade, many
studies have set out to find an appropriate biomarker for the diagnosis of AD.
6
This chapter starts with an overview as regards the most promising cerebro-
spinal fluid (CSF) biomarkers for the early and differential diagnosis of AD.
Next, the relationship of the biomarkers and atrophy on MRI is discussed.
Finally, limitations and topics for future research are presented.
Neuropathology
The basis for the research on biochemical markers are the neuropathologic
changes present in the various types of dementias.
7
Neuropathologic hall-
marks of AD – accumulation of extracellularly senile plaques (SPs) and
neurofibrillary tangles (NFTs), synaptic reductions, and neuron loss – gradual-
ly accumulate in time, and start long before the clinical picture of AD becomes
overt.
8
SPs are divided into two types: diffuse and neuritic plaques. The neu-
ritic plaques are composed of the highly insoluble fibrillar protein amyloid β
42
(Aβ
42
). Aβdepositions tend to accumulate with age. NFTs are intraneuronal
accumulations of abnormally (hyper)phosphorylated tau protein. NFTs can be
found already in non-demented subjects in the hippocampus and entorhinal
17
2
Cerebrospinal fluid markers for the
diagnosis of Alzheimer’s disease
Niki Schoonenboom, Harald Hampel, Philip Scheltens, and Mony de Leon
02-Chapter 2 5 8/31/05 11:09 AM Page 17

33. cortex (EC), the regions affected earliest in AD. SPs are found initially in the
neocortex, but in later stages they also affect the EC and the hippocampus.
9,10
Patients with frontotemporal dementia (FTD) show heterogeneity in underly-
ing pathology,
11
with tau deposits in some of them. Creutzfeldt–Jakob disease
(CJD) is characterized by spongiform changes, neuronal loss, gliosis and
immunostaining of the protease-resistant prion protein.
12
Dementia with Lewy
bodies (DLB) is part of the α-synucleinopathies, in which α-synuclein accu-
mulates in the intraneuronal Lewy bodies.
13
Vascular dementia (VAD) is char-
acterized by ischemic lesions, lacunes, and extensive white matter changes.
14
Between the different types of clinically diagnosed dementias significant
neuropathologic overlap exists.
15
Lewy bodies are present in AD, whereas
FTD, VAD and DLB plaques and tangles can be found. White matter changes
are found in all types of dementia, especially in AD.
16
CEREBROSPINAL FLUID AMYLOID β
42
AND TAU IN
ALZHEIMER’S DISEASE VS CONTROLS
According to criteria established in 1998, a good biomarker has to have a
sensitivity of at least 85% for AD and a specificity of ≥75% to differentiate AD
from other types of dementia.
7
The most promising CSF markers to differenti-
ate AD from non-demented elderly are Aβ
42
and tau. Below, each biomarker is
discussed separately. Next, the most valid studies will be summarized for the
combination of CSF Aβ
42
and tau.
Aβ
42
In numerous studies it has been shown that Aβ
42
is decreased in CSF of AD
patients compared with non-demented controls.
6,17
The decrease of Aβ
42
con-
centration in CSF is thought to be the result of several mechanisms:
1. deposition of insoluble Aβ
42
in the SP of the brain, which might be in part
the result of disturbance of the clearance of Aβ
42
2. decrease of production of Aβ
42
by less (active) neurons, inevitably a result
of neurodegeneration
3. altered binding to Aβ
42
-specific proteins (e.g. Apo E), resulting in masking
of the epitope, to which the antibodies of the assays are directed.
The decrease of CSF Aβ
42
concentration in AD is about 50% of that recorded
in controls.
17
The most commonly used assay is the commercial ELISA of
Innogenetics (Table 2.1). The median values of Aβ
42
, as measured in two large
case-control studies, are:
βAD = 487 (394–622) pg/ml, controls = 849 (682–1063) pg/ml;
18
β
AD = 394 (326–504) pg/ml, controls = 1076 (941–1231) pg/ml.
19
.
18ALZHEIMER’SDISEASE ANDRELATEDDISORDERSANNUAL
02-Chapter 2 5 8/31/05 11:09 AM Page 18

34. CSF MARKERS FORDIAGNOSIS19
Study Population
a
Gold standard
b
Criteria
c
Result Cut off Method
Galasko et al, 1998
22
82 probable AD Clinical diagnosis NINCDS– Sensitivity 77% Aβ
42
: 1032 pg/ml Aβ
42
and tau: in-
60 controls (1A) ADRDA Specificity 93% Tau: 503 pg/ml house methods
Multicenter study
Kanai et al, 1998
34
93 probable AD Clinical diagnosis NINCDS– Sensitivity 40% Aβ
42
: 256 fmol/ml Aβ
42
: in-house
41 controls (1A) ADRDA Specificity 90% Tau: 474 pg/ml method
Tau: Innogenetics
Hulstaert et al, 1999
18
150 probable AD Clinical diagnosis NINCDS– Sensitivity 85% Aβ
42
: 643 pg/ml Aβ
42
and tau:
100 controls = (1A) ADRDA Specificity 86% Tau: 252 pg/ml Innogenetics
42 HC + 58 ONDMulticenter study
Tapiola et al, 2000
23
80 probable AD Clinical (1A) and NINCDS– Sensitivity 46–53%
d
Aβ
42
: 340 pg/ml Aβ
42
: in-house
41 definite AD neuropathologic ADRDA Specificity 95% Tau: 380 pg/mlL method
39 OND diagnosis (IA) CERAD Tau: Innogenetics
Andreasen et al, 2001
35
105 probable AD Clinical diagnosis NINCDS– Sensitivity 94% Aβ
42
: 643 pg/ml Aβ
42
and tau:
100 controls of (1A) ADRDA Specificity 89% Tau: 252 pg/ml Innogenetics
Hulstaert et al.
18
Riemenschneider et al, 74 probable AD Clinical diagnosis NINCDS– Sensitivity 92% Aβ
42
: 738 pg/ml Aβ
42
and tau:
2002
19
40 controls (1A) ADRDA Specificity 95% Tau: 255 pg/ml Innogenetics
a
Probable AD = AD according to the clinical NINCDS–ADRDA criteria; definite AD = AD confirmed at neuropathologic examination; ON D = other neurologic diseases.
b
1A = clinical diagnosis is gold standard, prospective collected materials, including groups of patients and controls with a min imum of 30 individuals; IA = neuropathologic diagnose is gold
standard, rest conform to class 1A.
c
NINCDS–ADRDA = National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer’s Disease and Related Disorde rs Association.
d
Definite and probable AD vs OND.
Table 2.1 Diagnostic accuracy of cerebrospinal fluid (CSF) A β
42
and tau combined in Alzheimer’s disease (AD)
vs controls
02-Chapter 2 5 8/31/05 11:09 AM Page 19

35. 20ALZHEIMER’SDISEASE ANDRELATEDDISORDERSANNUAL
Study Population
a
Gold standard
b
Criteria
c
Result Cut off Method
Kapaki et al, 2003
24
49 probable AD Clinical diagnosis NINCDS– Sensitivity 96% Aβ
42
: 490 pg/ml Aβ
42
and tau:
49 controls (1A) ADRDA Specificity 86% Tau: 317 pg/ml Innogenetics
3 year follow-up
Sunderland et al, 2003
6
131 probable AD Clinical diagnosis DSM-IV Sensitivity 92% Aβ
42
: 444 pg/ml Aβ
42
: in-house
72 controls (1A) NINCDS– Specificity 89% Tau: 195 pg/ml method
ADRDA Tau: Innogenetics
a
Probable AD = AD according to the clinical NINCDS–ADRDA criteria; definite AD = AD confirmed at neuropathologic examination; ON D = other neurologic diseases.
b
1A = clinical diagnosis is gold standard, prospective collected materials, including groups of patients and controls with a min imum of 30 individuals; IA = neuropathologic diagnose is gold
standard, rest conform to class 1A.
c
NINCDS–ADRDA = National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer’s Disease and Related Disorde rs Association.
d
Definite and probable AD vs OND.
Table 2.1 Continued
02-Chapter 2 5 8/31/05 11:09 AM Page 20

36. Reference value for CSF Aβ
42
obtained from a control population is set above
500 pg/ml.
20
Sensitivity ranged from 69–100%, whereas specificity ranged
from 56–85% in a subset of studies.
19,21–25
Considerable variability in absolute
levels of Aβ
42
exists among centers, even when using the same commercial
assay. Cross-sectional studies show little evidence of a relationship between
CSF Aβ
42
and age, except for one study showing a U-shaped natural course in
normal aging, with an increase of CSF Aβ
42
until 29 and over 60 years old.
26
No
18,23
or only a weak
22
cross-sectional relationship has been found between
CSF Aβ
42
and disease duration or Mini-Mental State Examination (MMSE).
Only one study investigated and found an association between the number of
SPs and the CSF Aβ
42
concentration.
27
Tau
Many studies have demonstrated that tau is increased in CSF of AD patients;
concentrations are about three times higher in AD than in non-demented con-
trols. However, there is a large variation in the range of CSF tau concentration
in AD. Median and mean concentrations of CSF are 425 (274–713) pg/ml and
587 (365) pg/mL in AD, and 195 (121–294) pg/mL and 224 (156) pg/ml in
controls.
6,18
The increase of tau in CSF is supposed to be the result of release
from dying neurons containing a large number of NFTs. One study demon-
strated that CSF tau concentration was related to the number of NFTs in the
brain.
28
Again, the most commonly used assay for tau is the ELISA from
Innogenetics (Table 2.1). Mean sensitivity ranged from 55 to 81% at a mean
specificity value of 90% comparing AD with controls.
17
Important is that CSF
tau increases with age,
19,29
which stresses the need to compare only groups
from the same age category.
30
Furthermore, CSF tau tends to be increased in
several other neurologic disorders, such as acute stroke
31
and trauma,
32
indi-
cating that the marker is not very specific. Reference values for tau in healthy
individuals are defined as <300 pg/ml (21–50 years old); <450 pg/ml (51–70
years old); and <500 pg/ml (71–93 years old).
19
No correlation was found
between CSF tau and MMSE or disease duration.
Combination of CSF Aβ
42
and tau
Diagnostic accuracy, especially the specificity, increases when using the combi-
nation of CSF Aβ
42
and tau comparing AD with controls, including patients
with depression or memory problems due to alcohol abuse.
17
In Table 2.1 an
overview is given of class IA and 1A case-control studies, with neuropatho-
logic (IA) or clinical diagnosis (1A) as gold standard, and patient and control
groups included with a minimum of 30 individuals.
33
CSF MARKERS FORDIAGNOSIS21
02-Chapter 2 5 8/31/05 11:09 AM Page 21

37. Isoprostanes
Oxidative stress is thought to play an important role in the cascade, resulting
in cell death in AD.
36
A few studies have demonstrated that isoprostanes are
increased in CSF of AD patients, even at an early stage of disease.
37,38
Further
studies are needed on how these proteins can be used in the diagnostic work
up for AD, especially to clarify the specificity of these markers.
CEREBROSPINAL FLUID MARKERS IN ALZHEIMER’S
DISEASE VS OTHER DEMENTIAS
Combination of CSF Aβ
42
and tau
How good is the diagnostic accuracy when using the combination of Aβ
42
and
tau in AD compared with other types of dementias? Although this topic is
much more relevant for clinical practice, only a few studies investigated these
two markers in large groups of patients. Most studies found a lower specificity
as compared to the studies mentioned in Table 2.1. There is substantial over-
lap in CSF Aβ
42
and tau concentrations between different types of dementias.
A decreased concentration of CSF Aβ
42
can be found in DLB, FTD, and
VAD.
18,20,30,39
A high CSF tau is also not specific for AD: CSF tau is found to
be increased in a subset of FTD and VAD patients.
18,30
In most cases of DLB,
CSF tau concentration is normal.
39
In CJD, CSF Aβ
42
is decreased and CSF tau
is found to be very high, even higher than in AD.
40
The specificity of the com-
bined CSF Aβ
42
/tau analysis varies from 85%, comparing AD with FTD, to
67%, in AD vs DLB, and 48%, in AD vs VAD (Table 2.2).
Phosphorylated tau
Several investigators have developed assays to detect phosphorylated tau
(Ptau) in CSF. As NFTs have an abundance of abnormally phosphorylated tau,
it is to be expected that Ptau is increased in CSF from AD patients. Several
immunoassays have been developed that are specific for the phosphorylated
epitopes threonine 181 (Ptau-181),
41
serine 199 (Ptau-199),
42
and threonine
231 (Ptau-231).
43
Good results have been obtained comparing AD with other
types of dementia; in the majority of patients, Ptau is found to be normal in
DLB,
44
VAD,
45
FTD,
30
and CJD.
46
One study demonstrated an increase in diag-
nostic accuracy of Ptau-231 and Ptau-181 compared to Ptau-199 in differenti-
ating AD from other types of dementia.
47
The same authors found a decline of
CSF Ptau-231 during the course of AD in 17 patients.
48
These data need to be
confirmed in another independent study, preferably with postmortem confir-
mation of diagnoses. A greater diagnostic accuracy of Ptau compared with
total tau is obtained in most studies.
30,49
In one study it has been shown that
the combination of CSF Aβ
42
with Ptau-181 differentiated best early onset AD
(EAD) from FTD with a high specificity (93%) and a low negative predictive
22ALZHEIMER’SDISEASE ANDRELATEDDISORDERSANNUAL
02-Chapter 2 5 8/31/05 11:09 AM Page 22

38. CSF MARKERS FORDIAGNOSIS23
Study Population
a
Gold standard
b
Criteria
c
Result Cut off
Galasko et al, 1998
22
82 probable AD Clinical diagnosis (1A) NINCDS–ADRDA Sensitivity 77% Aβ
42
: 1032 pg/ml
74 NAD Specificity 65% Tau: 503 pg/ml
Hulstaert et al, 1999
18
150 probable AD Clinical diagnosis (1A) NINCDS–ADRDA Sensitivity 85% Aβ
42
: 643 pg/ml
79 NAD Specificity 58% Tau: 252 pg/ml
Tapiola, 2000
23
80 probable AD Clinical (1A) and NINCDS–ADRDA Sensitivity 50% Aβ
42
: 340 pg/ml
41 definite AD neuropathological CERAD Specificity 85% Tau: 380 pg/ml
27 NAD diagnosis (IA)
Andreasen et al, 2001
35
105 probable AD Clinical diagnosis (1A) NINCDS–ADRDA Sensitivity 94% Aβ
42
: 643 pg/ml
23 VAD VAD: NINDS–AIREN Specificity VAD 48% Tau: 252 pg/ml
9 DLB DLB: McKeith Specificity DLB 67%
Riemenschneider 74 probable AD Clinical diagnosis (1A) NINCDS–ADRDA Sensitivity 85% Aβ
42
: 528 pg/ml
et al, 2002
19
34 FTLD FTLD: Neary Specificity 85% Tau: 432 pg/ml
Kapaki et al, 2003
24
49 probable AD Clinical diagnosis (1A) NINCDS–ADRDA AD vs NAD:
15 NAD VAD: NINDS–AIREN Sensitivity: 71–90% Aβ
42
: 435 pg/ml
6 VAD AD vs NAD/VAD: Specificity: 83–100% Tau : 437 pg/ml
Schoonenboom et al, 47 probable EAD Clinical diagnosis (1A) NINCDS–ADRDA Sensitivity 72% Aβ
42
: 413 pg/ml
2004
30
28 FTLD FTLD: Neary Specificity 89% Tau: 377 pg/ml
a
Probable AD = AD according to the clinical NINCDS–ADRDA criteria; definite AD = AD confirmed at neuropathologic examination; EA D = early-onset AD, disease starting before 65 years
old; VAD = vascular dementia; DLB = diffuse Lewy body disease; FTLD = frontotemporal lobar degeneration; NAD = non-Alzheimer de mentia.
b
1A = clinical diagnosis is gold standard, prospective collected materials, including groups of patients and controls with a min imum of 30 individuals; IA = neuropathologic diagnosis is gold
standard, rest conform to class 1A.
c
NINCDS–ADRDA = National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer’s Disease and Related Disorde rs Association. CERAD = Consortium to Establish a
Register for Alzheimer’s Disease. AIREN = Association Internationale pour la Recherche et l’Enseignement en Neurosciences.
Table 2.2 Diagnostic accuracy of cerebrospinal fluid (CSF) and tau combined in Alzheimer’s disease (AD)
vs other types of dementia
02-Chapter 2 5 8/31/05 11:09 AM Page 23

39. value (negative likelihood ratio=0.03).
30
As there still exists overlap between
the different types of dementia, either clinically or biochemically, a combina-
tion of the three markers seems best for routine clinical practice, with at least
two of the three biomarkers positive as indicator for AD.
50
14-3-3 protein
The 14-3-3 protein gives, like tau, a reflection of (fast progressive) neuron
loss. It can be detected in CSF by the semiquantitative Western blot analysis.
When used in the proper context, with a high clinical suspicion and in combi-
nation with electroencephalography (EEG), MRI scan, and routine CSF analy-
sis, the measurement of 14-3-3 protein in CSF supports the diagnosis of CJD
with high diagnostic accuracy.
51
False-positive results can be obtained in acute
stroke, brain tumor, encephalitis, or even (fast progressive) AD. Sensitivity
and specificity values of CSF 14-3-3 and tau have been reported to be the same
in one study (cut-off level for tau=1300 pg/ml).
52
Recently, it has been shown
that the combination of 14-3-3 protein and Aβ
42
gives the highest diagnostic
accuracy for CJD (sensitivity 100%, specificity 98%, positive predictive value
93%, negative predictive value 100%).
40
GOLD STANDARD
The majority of the above-mentioned studies have been obtained in groups of
patients where the diagnosis has been obtained clinically. The accuracy of the
clinical diagnosis in specialized settings is estimated at around 85%.
53
By use
of clinical criteria, there is risk of circular reasoning: i.e. the diagnostic
performance of CSF markers cannot be higher than the accuracy of the clinical
criteria.
17
The NINCDS/ADRDA (National Institute of Neurological and
Communicative Diseases and Stroke/Alzheimer’s Disease and Related
Disorders Association) criteria for AD have a high sensitivity but a moderately
high specificity. Illustrative is the specificity of only 23% of the
NINCDS/ADRDA criteria for the differentiation of AD from FTD in one retro-
spective neuropathologic study.
54
Furthermore, 40–80% of the clinically diag-
nosed VAD patients have concomitant AD pathology.
55
Only two studies were
published in which (in part) the neuropathologic diagnosis was used as gold
standard.
23,56
For the differentiation of AD from controls, similar sensitivity
and specificity were obtained for CSF tau and Aβ
42
as compared to clinical
studies (Table 2.1).
23
However, the specificity of FTD and DLB compared with
AD was not optimal, 69%.
56
Most published studies were performed in specialized tertiary referral set-
tings with selected patient groups. Only a few studies were carried out with
consecutively recruited patients from a memory clinic; sensitivity was high,
but specificity was lower in this setting with ‘unselected’ patients.
35,57
More
studies are needed in large primary and secondary referral centers to obtain an
24ALZHEIMER’SDISEASE ANDRELATEDDISORDERSANNUAL
02-Chapter 2 5 8/31/05 11:09 AM Page 24

40. insight into how to use CSF Aβ
42
, tau, and Ptau in an elderly population in
clinical practice. Population-based studies are under way to establish CSF
markers as potential biomarkers for routine diagnostic use
MILD COGNITIVE IMPAIRMENT
Mild cognitive impairment (MCI) is considered to be a transitional state
between normal aging and dementia. Around 10–15% of MCI patients
progress to Alzheimer-type dementia each year.
58
Several studies have shown
that a subgroup of MCI patients has low CSF Aβ
42
levels and/or high CSF tau
levels at baseline that are indicative for AD.
17
Furthermore, there is evidence
that these markers can be used as predictors for the conversion of MCI to
AD.
50,59
It is not clear yet which marker is changed first in the disease process,
as contradictory findings are reported by various studies describing either an
increased CSF tau
50,60
or a decreased CSF Aβ
42
at baseline.
61,62
In two inde-
pendent studies a relationship between CSF tau with memory impairment was
found, whereas this was not the case for CSF Aβ
42
.
63,64
Good results have been
obtained for CSF Ptau as an indicator of AD-related changes in the MCI
stage.
4,59,65
In one study it has been demonstrated that high CSF levels of Ptau
at baseline, but not CSF tau levels, correlated with cognitive decline and con-
version of MCI to AD.
66
A very recent study, following 78 MCI patients, shows
the best prediction for the development of AD using the combination of CSF
Aβ
42
with Ptau.
67
Most of the studies mentioned have been conducted retro-
spectively in research settings, and limited data are available about the fre-
quency of a biomarker profile typical for AD in a prospective setting that
reflects clinical practice. But, overall, the use of biomarkers in combination
with other diagnostic tools is very promising in recognizing MCI patients who
will develop AD in the future.
NEUROIMAGING AND CEREBROSPINAL FLUID
BIOMARKER STUDIES
Cross-sectional studies
Hippocampal size reduction, atrophy of the medial temporal lobe (MTL), and
the entorhinal cortex (EC) are sensitive markers for AD. Moreover, atrophy of
the hippocampus is found to be a good predictor in MCI for the development
of AD. However, these markers are not disease-specific and cannot be used as
primary evidence for AD.
4
By combining CSF and MRI markers, one could get
a better diagnostic accuracy. In addition, by investigating the relationship
between the two markers a better understanding of the agreement between the
two disease markers could be obtained: do they reflect the same pathologic
substrate at the same time? Only a few studies have investigated the cross-
CSF MARKERS FORDIAGNOSIS25
02-Chapter 2 5 8/31/05 11:09 AM Page 25

41. sectional relationship between CSF biomarkers and atrophy on MRI in small
groups of patients. One study showed a correlation between CSF Aβ
42
and the
volume of the temporal lobes.
68
We were unable to find a relationship between
atrophy of the MTL and CSF Aβ
42
, tau, and Ptau in 62 mild–moderate AD
patients and 32 controls when considered as separate groups.
69
Moreover,
both disease markers contributed independently to the diagnosis of AD. In
MCI patients, we found a relationship between CSF Aβ
42
and atrophy of the
MTL, whereas CSF tau did not relate to MTA.
63
These data corresponded to a
larger study reporting lower baseline CSF Aβ
42
levels with lower brain volume
and larger ventricular volume in the spectrum of normal aging, MCI, and
AD.
70
In contrast, higher CSF tau and Ptau were found with an increase in
ventricular widening during follow-up. In this light, CSF Aβ
42
can be more
considered as astagemarker, indicating the presence of disease at a certain
time, whereas CSF tau is more a statemarker, indicating the intensity of the
neuronal damage and degeneration.
17,70
However, these data give only infor-
mation about one time point in the disease, and until now it has not been pos-
sible to show progressive changes in CSF Aβ
42
or Ptau concentrations, except
for one study.
71
On the other hand, atrophy rates on MRI are good indicators
of disease progression in MCI and AD. The question is therefore: can both dis-
ease markers be used as markers of progression?
Longitudinal studies
The few studies investigating the change in CSF biomarkers were carried out
on AD patients. Little is known about the change of CSF Aβ
42
, tau, and Ptau
in MCI, whereas one would expect that in this early stage of disease the bio-
markers would be more prone to change than in later stages. One study inves-
tigated whether there was a longitudinal relationship between the change in
biomarkers with the change in hippocampal volume on MRI in a small group
of aged individuals with and without memory problems.
4
In a two time-point
longitudinal design, the MCI group, n= 8, showed an inverse relationship
between hippocampal volume reductions and elevations in CSF Ptau, whereas
CSF Aβ
42
levels showed a positive relationship with hippocampal volume
reductions. However, there are several limitations of this study:
βa very small group was investigated
βit is not known whether these MCI patients will develop AD
βand the change in biomarkers could also be due to the intra-assay vari-
ability, as very small changes are detected.
Indeed, the authors did not find a significant change in CSF Aβ
42
, and Ptau
concentrations between two time points if they corrected for dilution of tau
due to ventricular enlargement; this ‘Ptau-231 load’ was increased in MCI at
follow-up.
65
These findings need to be replicated in larger groups of patients;
in addition, further studies are warranted for a better understanding of the
CSF flow and clearance dynamics of biomarkers.
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42. ADDED VALUE OF CEREBROSPINAL FLUID
MARKERS OVER OTHER DIAGNOSTIC TOOLS
In a recent review the position of CSF markers in the clinical assessment of
patients with MCI and early AD has been discussed.
17
The authors suggest
that only after intensive screening of the patients by history, neurologic exami-
nation, routine laboratory tests (blood and CSF), and neuroimaging (comput-
ed tomography (CT), MRI, or single-photon emission computed tomography
(SPECT)) is there a place for CSF markers for the (early) diagnosis of AD. The
clinical diagnosis of AD should be based on the cumulative information of all
the different diagnostic tools, as in other areas of medicine. For the differential
diagnosis of AD, we state that the biomarkers are especially important for the
early-onset dementias, as there is clinical and radiologic overlap, especially
between EAD and FTD. In the older age group, the prevalence of AD is much
higher, and the usefulness of biomarkers to distinguish AD from other types of
dementia becomes less relevant. However, since the currently available med-
ications to enhance cognition are approved for mild to moderate AD, every
hint to the correct diagnosis should be taken into account irrespective of age.
The added value of CSF markers over other diagnostic tools has not yet been
investigated systematically, and is an aim for future studies.
LIMITATIONS OF RESEARCH ON CEREBROSPINAL
FLUID MARKERS
For the differentiation of AD from normal aging, depression, or other types of
dementia, overlap is seen in CSF Aβ
42
, tau, and Ptau concentrations between
the groups. One explanation is that the control or demented groups could
have neuropathologic findings indicative for AD, resulting in an AD biomarker
profile. It is also not yet clear whether the decrease of CSF Aβ
42
and the
increase of (P)tau actually reflect the plaques and tangles in AD. Other expla-
nations are the use of different processing and storage conditions of CSF
between different centers,
72
the use of different reagent antibodies, differences
in the definition of cut-off values, and intra- and inter-assay variability of the
assays used.
17
Standardization of the (pre-) analytical methods will increase
the reliability of the results and improve collaboration with other
neurologic/biochemical research centers or memory clinics. Although it is not
difficult to obtain CSF by lumbar puncture, this method is considered to be
somewhat invasive for an outpatient clinic, especially in the USA. Therefore, a
sensitive serum or plasma marker for AD would be very valuable for use in
clinical practice.
CSF MARKERS FORDIAGNOSIS27
02-Chapter 2 5 8/31/05 11:09 AM Page 27

43. CONCLUSION
For the differentiation of AD from normal aging, depression, or alcoholic
dementia, the combination of CSF Aβ
42
with tau gives a high sensitivity and
specificity of ≥85%, with minimal overlap in individual cases. In the pre-clini-
cal (MCI) stage of disease, CSF Aβ
42
, tau, and Ptau could be used as predictors
for the development of AD. For the differentiation of AD from other types of
dementia, the combination of CSF Aβ
42
, tau, and Ptau gives a good sensitivity
and a reasonable specificity, especially for the differentiation of AD from FTD
and less for AD vs DLB or VAD. For clinical practice, a high positive predictive
value and a low negative predictive value are important. With at least two
markers positive, the diagnosis of AD is very likely, while two markers nega-
tive could practically rule out diagnosis of AD. The CSF biomarkers must only
be used in combination with other diagnostic tools, including clinical history
and examination, imaging, and neuropsychologic work-up.
Guidelines for the use of CSF Aβ
42
, tau and Ptau in clinical
practice
1. When there is doubt about the diagnosis AD, with non-conclusive MRI or
neuropsychological findings.
2. In patients with early-onset dementias (disease onset before 65 years old),
as the differential diagnosis here is wider and more complicated; in particu-
lar, the differentiation of EAD from FTD is relevant.
3. In patients suspected for CJD, in combination with CSF 14-3-3 protein,
MRI scan, and EEG.
Topics for future research
βInvestigate the additional value of the biomarkers CSF Aβ
42
, tau, and Ptau
to other diagnostic methods, i.e. MRI parameters and/or neuropsychologic
examinations.
βInvestigate the diagnostic value of the biomarkers in primary and second-
ary referral settings, preferably with neuropathologic or prolonged clinical
follow-up.
βInvestigate which markers could be used for tracking the progression of
the disease, especially in the MCI stage of disease. Promising markers are
C- and N-terminally truncated Aβpeptides, oxidative stress markers or
inflammatory markers.
βDevelop new tests for a sensitive marker that can be determined in blood
or urine.
βStandardize (pre-analytical) laboratory methods between research centers.
28ALZHEIMER’SDISEASE ANDRELATEDDISORDERSANNUAL
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49. 02-Chapter 2 5 8/31/05 11:09 AM Page 34

50. INTRODUCTION
The term ‘mild cognitive impairment’ (MCI) has been applied to non-
demented elderly persons with isolated cognitive and minimal functional
impairment.
1
It is widely held that MCI progresses towards dementia, presum-
ably that of Alzheimer’s disease (AD).
2
For the purposes of MCI case finding, cognitive ‘impairment’ is most often
defined by a performance 1.0–1.5 standard deviations below an age-specific
norm. When applied to memory test scores, this definition results in the selec-
tion of cases with an increased risk of dementia conversion. In an evidence-
based review of MCI, the American Academy of Neurology cited six papers
reporting conversion rates ranging from 6–25% per year.
2
Although memory impairment has been the major focus of MCI research, it
is increasingly clear that non-amnestic MCI syndromes also exist.
3
Whether
non-amnestic MCI progresses to AD is debatable. AD pathology – i.e. neuro-
fibrillary tangles (NFTs) and paired-helical filament tauopathy
*
– is hierarchi-
cally distributed in space, and presumably time.
4
The hippocampus is affected
relatively early in this progression. This explains both the significance of isolated
memory impairment as a harbinger of future AD, and the fact that memory
impairment is almost universally present among cases with AD, as opposed to
certain non-AD dementias. However, the hierarchical distribution of AD pathol-
ogy also suggests that non-amnestic MCI is not likely to be AD related.
Impairment of executive control function (ECF) is likely to be common
among persons diagnosed with MCI. First, ECF impairment is present both
early in AD, but particularly in non-AD dementias. Secondly, it is increasingly
clear that ECF impairment is common in medically ill and community-
dwelling older persons at risk to be diagnosed with MCI.
35
3
Executive control function in ‘mild’
cognitive impairment and Alzheimer’s
disease
Donald R Royall
*
Senile plaque (SP) and β-amyloid are more randomly distributed and not always co-
localized with NFT. However, regional NFT counts are more strongly correlated with
AD’s clinical features than are SP and fully mediate SP’s unadjusted associations with
cognition in multivariate models.
03-Chapter 3 5 8/31/05 11:23 AM Page 35

51. However, ECF, rather than memory loss, appears to a major predictor of
functional outcomes. Thus, the issue of ECF impairment has implications for
dementia case-finding that go well beyond ‘MCI’. In contrast to memory or
other non-executive cognitive impairments, the presence of ECF impairment
suggests disability, and thus ‘dementia’ as well. The recognition of ECF impair-
ment as being ‘essential’ to dementia would have far-ranging consequences for
the epidemiology of that condition.
This chapter examines the issue of ECF impairments in both AD and MCI
and considers the following questions:
βIs ECF impairment present in AD?
βIs ECF impairment reported in ‘MCI’?
βIs ECF impairment likely to be present in ‘amnestic’ MCI?
βCan ECF impairment be observed in the absence of disability?
βIs isolated ECF impairment a true ‘dementia’?
IS EXECUTIVE CONTROL FUNCTION IMPAIRMENT
PRESENT IN ALZHEIMER’S DISEASE?
There is good reason to suspect that ECF impairment is present from the out-
set of clinicalAD. First, frontal cortical AD pathology is more strongly related
to cognitive impairment than are lesions in other regions of interest (ROIs).
Plaques and tangles counted in the frontal cortex explain almost twice as
much variance in cognition than do the same lesions in other ROIs.
5
Frontal
lobe synaptic density is the strongest reported pathologic correlate of cognitive
impairment in the AD literature.
6
In contrast, hippocampal AD pathology is
relatively weakly associated with cognition, and may have no association with
clinical dementia, independent of frontal lesions.
5
A few multivariate models have been published that specifically associate
regional AD pathology with clinical features of dementia. Geddes et al
7
factor-
analyzed the regional distribution of NFTs. Two factors were identified. The
first contained only mesiotemporal ROI, affected before Braak stage IV. This
factor was significantly associated with memory impairment, but not demen-
tia. In contrast, dementia was more closely associated with pathology in neo-
cortical ROI, including the frontal cortex. Royall et al
8
modeled the individual
contribution of regional tauopathy with clinical ‘dementia’, defined by a
Clinical Dementia Rating (CDR) scale
9
score ≥1.0. The hippocampus was the
only ROI whose pathology had no unadjusted association with dementia.
‘Dementia’ was most strongly associated with pathology in only four ROI,
including the dorsolateral prefrontal cortex (Brodmann area (BA) 9/10), the
angular gyrus (BA 39), the posterior cingulate (BA 23), and the superior tem-
poral gyrus (BA 22). Each is retrogradely labeled by an excitotoxic lesion to
the dorsolateral prefrontal cortex,
10
suggesting that they (and the anterior cin-
gulate, not available to Royall et al
8
) comprise a single system focused on the
36ALZHEIMER’SDISEASE ANDRELATEDDISORDERSANNUAL
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52. executive control of complex behavior.
11
Diminished cerebral blood flow
(rCBF), by functional magnetic resonance imaging (fMRI), in the same ROI,
distinguishes AD, and apolipoprotein E (APOE) ε4 homozygotes, from non-
demented elderly controls.
12
Dementia can be diagnosed before the appearance of NFTs in neocortical
ROIs.
13
However, this may require comorbid pathology.
11
In dementia cases,
Braak stage is inversely related to the severity of comorbid ischemic cere-
brovascular disease (ICVD)
14
and only a fraction of demented persons have
onlyAD pathology at autopsy.
15
Moreover, the ischemic lesions with the
strongest associations to cognition may be too small to image by computed
tomography (CT) or MRI. Thus, ‘mixed’ cases may be misascribed to ‘AD’.
16
However, since clinical dementia can also be specifically associated with
‘strategic’ infarcts involving the very same neocortical ROIs as AD,
17
and since
neocortical function can be vicariously affected by subcortical frontal system
lesions (i.e. through diaschisis)
18
it seems likely that clinical ‘AD’ is associated
with frontal system dysfunction regardless of whether neocortical ROIs have
been directly affected by AD pathology, or indirectly affected by comorbid
ICVD.
19
Nevertheless, there are surprisingly few data on ECF impairment in AD.
Older studies either ignore this domain entirely, or use measures that have
little sensitivity to ECF. Some more recent studies include executive measures.
Lowenstein et al.
20
failed to find significant associations between some ECF
measures – i.e. verbal fluency, digit-symbol substitution, or Weschler Adult
Intelligence Scale (Revised) (WAIS-R) similarities – and the Direct Assessment
of Functional Status (DAFS) in AD cases. Willis et al.
21
reported that ECF
measures add variance to functional outcomes above that attributed to ‘gener-
al’ cognitive measures, but the additional variance explained was relatively
small. Chen et al.
22
reported signifiant associations between Mattis Dementia
Rating Scale (mDRS) ‘initiation /perseveration’ (I/P), mDRS ‘conceptualiza-
tion’, and the number of categories achieved on the Wisconsin Card Sorting
Test (WCST:CAT) and Blessed Dementia Scale: Activities subscale (BDS-A).
Boyle et al.
23
report that the mDRS I/P explains 17% of variance in IADL
(Instrumental Activities of Daily Living), and 9% of variance in ADL
(Activities of Daily Living), independent of ‘apathy’ as measured by the
Frontal System Behavior (FrSBe) scale.
In contrast, Marson et al.
24
report that mDRS I/P explained 36% of the vari-
ance in a ‘rational reasons’ standard of medical decision-making among AD
patients. Similarly, the same group reported that verbal fluency explained 58%
of variance in an ‘Appreciating Consequences’ standard.
25
These studies suggest that although ECF impairment can be demonstrated
in AD, its association with functional status varies widely with both the specif-
ic ECF measure employed and the functional outcome under consideration.
IADL may be more strongly related to ECF than ADL, but ECF is most
strongly related to ‘higher’ functional capacities, such as decision-making.
EXECUTIVECONTROLFUNCTION INMCIANDAD37
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53. IS EXECUTIVE CONTROL FUNCTION IMPAIRMENT
REPORTED IN MILD COGNITIVE IMPAIRMENT?
Very few studies have specifically addressed ECF impairment in the context of
MCI. Nagahama et al.
26
factor-analyzed WCST performance in a small number
of AD and MCI cases. Both groups were more executively impaired than nor-
mal controls, but they were not discriminable from each other on the basis of
their perseverative errors. The MCI group actually made significantly more
non-perseverative errors than the AD group. Similarly, Ready et al.
27
studied
the rate of change in ECF-related behaviors (i.e. apathy, ‘executive dysfunc-
tion’, and disinhibition) in AD and MCI. Apathy and ‘executive dysfunction’
both increased over time, but MCI could not be distinguished from AD on the
basis of these changes. Thus, it appears that ECF impairments comparable to
AD can develop in the absence of a clinical diagnosis of ‘dementia’.
To some extent, this is an artifact of dementia case definitions themselves.
These emphasize the clinical detection of AD at the expense of non-AD condi-
tions.
28
By definition, isolated ECF impairment cannot be classified as ‘demen-
tia’ by either the DSM (Diagnostic and Statistical Manual)
29
or the NINCDS
(National Institute of Neurological and Communicative Diseases and
Stroke),
30
due to the absence of memory impairment. Conversely, clinical AD
is unlikely to cause ECF impairment unless and until the hippocampus is
affected at about Braak stage III.
This constraint forces researchers to place isolated ECF impairment into
“non-demented” diagnostic categories (e.g. Age-Associated Cognitive Decline
or Cognitive Impairment: No Dementia). A more subtle bias is the failure of
clinicians to consider dementia when the clinical features of AD (i.e. aphasia,
amnesia, and agnosia, which reflect a widespread cortical disease process) are
not present. For example, Schillerstrom et al
31
tested ECF in N= 50 medical
inpatients referred for psychiatric consultation (mean age = 44.9 ± 16.7 years).
Although 62% were executively impaired (including 100% of cases diagnosed
with dementia), only 22% were diagnosed by the psychiatrists as having cog-
nitive impairment. In the absence of AD’s clinical features, the consultants
failed to recognize ECF’s contribution to the other cases’ behavioral changes.
Schillerstrom et al.
31
used the Executive Interview (EXIT25)
32
to identify
patients with ECF impairment. The EXIT25’s threshold for impairment (i.e.
15/50) is not age-adjusted. Instead, it was set to detect functional incapacity.
The EXIT25 has previously been shown to be a significant independent pre-
dictor of IADL
33
and level of care
33,34
among elderly retirees. Dymek et al.
35
have reported that the EXIT25 independently accounted for 56% of the vari-
ancein the capacity of patients with Parkinson’s disease to understand the cir-
cumstances and choices associated with their treatment, and 45% of the
variance in a ‘rational reasons’ standard of the capacity to give informed con-
sent. EXIT25 scores are also associated with medication adherence in medical
patients.
36,37
Allen et al.
37
report that, at a cut-point of 15 /50, the EXIT25
38ALZHEIMER’SDISEASE ANDRELATEDDISORDERSANNUAL
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54. perfectly distinguishes between elderly patients who can, and cannot, be
taught to competently use inhalers.
However, the mean EXIT25 score for non-institutionalized, affluent, well-
educated elderly retirees is about 12.5 /50.
33
Thus, although statistically ‘nor-
mal’ for their age, 38% will fail the EXIT25 at 15/50, compared with 25% of
community-dwelling young adults with schizophrenia,
38
19.9% of cancer
patients presenting for radiotherapy,
39
42% of consecutively admitted medical
inpatients,
40
and 59% of medical outpatients with type 2 diabetes mellitus.
41
Thus, ECF impairment sufficient to interfere with many aspects of healthcare
delivery is likely to be quite common in medical settings. Moreover, in each of
the studies cited above, Mini-Mental State Examination (MMSE) scores
42
were
within the normal range(i.e. ≤24/30). In the absence of formal ECF testing, the
lack of impairment in other domains can blind clinicians to the possibility of
disabling ECF impairment.
IS EXECUTIVE CONTROL FUNCTION IMPAIRMENT
LIKELY TO BE PRESENT IN ‘AMNESTIC’ MILD
COGNITIVE IMPAIRMENT?
Some authors distinguish between ‘amnestic’ MCI, in which the cognitive
impairments are limited to memory function, and more generalized ‘mild’ cog-
nitive impairments. Nonetheless, it is likely that many ‘amnestic’ MCI cases
actually do have both comorbid ECF impairments and disability. Depending
on the measures employed, 25–35% of ‘amnestic’ MCI cases can be shown to
have equally severe ECF impairment.
43
Such cases could arguably meet crite-
ria for ‘dementia’ were either their disability or their ECF to be more rigorous-
ly assessed. For example, whereas the slope of change in the memory test
scores of non-demented retirees is specifically associated with conversion to
cortical-type dementias,
44
and is accelerated by the APOE ε4 allele,
45
simulta-
neous changes in ECF mediate memory’s unadjusted association with changes
in functional status.
46
Aging is associated with disproportionate effects on the rate of change in
ECF.
47
Therefore, ECF impairment is so common in old age as to be statistical-
ly ‘normal.’ Thus, although only 4% of non-institutionalized retirees may have
ECF impairment at an age-specific threshold of 1.5 standard deviations below
the mean, 38%
48
have impairment at a level that perfectly distinguishes
patients who do, or do not have the capacity to learn to use an inhaler
37
or
accurately self-assess their financial decision-making capacity.
49
At present, MCI cases are most often distinguished from dementia solely on
the basis of a CDR score. However, this measure has not been validated as a
measure of disability, and may select for MCI cases which cannot be distin-
guished from dementia on the basis of their IADL.
50
EXECUTIVECONTROLFUNCTION INMCIANDAD39
03-Chapter 3 5 8/31/05 11:23 AM Page 39

55. Exploring the Variety of Random
Documents with Different Content

56. human parenthood is crowned with responsibility to the unborn, and
to all time coming, and that man, the animal in body, is also a self-
conscious being, “looking before and after,” who is human because
he is responsible, and to whom the laws of nature have been
revealed, not to satisfy an intellectual curiosity, but for the highest
end conceivable—the elevation of his race.
Let me quote a fine passage from Wordsworth's “Prelude”:—
“With settling judgments now of what would last
And what would disappear; prepared to find
Presumption, folly, madness, in the men
Who thrust themselves upon the passive world
As Rulers of the world; to see in these,
Even when the public welfare is their aim,
Plans without thought, or built on theories
Vague and unsound; and having brought the books
Of modern statists to their proper test,
Life, human life, with all its sacred claims
Of sex and age, and heaven-descended rights,
Mortal, or those beyond the reach of death;
And having thus discerned how dire a thing
Is worshipped in that idol proudly named
‘The Wealth of Nations’; where alone that wealth
Is lodged, and how increased; and having gained
A more judicious knowledge of the worth
And dignity of individual man,
No composition of the brain, but man
Of whom we read, the man whom we behold
With our own eyes—I could not but enquire—
Not with less interest than heretofore,
But greater, though in spirit more subdued—
Why is this glorious creature to be found
One only in ten thousand? What one is,
Why may not millions be? What bars are thrown
By Nature in the way of such a hope?”

57. Consider how far we have come, the base degrees by which we did
ascend, and answer with Shakespeare, “There are many events in
the womb of time which will be delivered.”
CHAPTER XVI
NATIONAL EUGENICS: MR. BALFOUR ON
DECADENCE
(1) “If the various checks specified in the two last paragraphs,
and perhaps others as yet unknown, do not prevent the reckless,
the vicious, and otherwise inferior members of society from
increasing at a quicker rate than the better class of men, the
nation will retrograde, as has too often occurred in the history of
the world. We must remember that progress is no invariable rule.
It is very difficult to say why one civilised nation rises, becomes
more powerful, and spreads more widely, than another; or why
the same nation progresses more quickly at one time than at
another. We can only say that it depends on an increase in the
actual number of the population, on the number of the men
endowed with high intellectual and moral faculties, as well as on
their standard of excellence. Corporeal structure appears to have
little influence, except so far as vigour of body leads to vigour of
mind.”—Daêïin, The Descent of Man, 1871.
(2) Referring to “the rates with which the various classes of
society (classified according to civic usefulness) have contributed
to the population at various times, in ancient and modern
nations,” Mr. Francis Galton said “there is strong reason for
believing that national rise and decline is closely connected with
this influence.”—Galton, Sociological Papers, 1904, p. 47.

58. (3) “The inexplicable decline and fall of nations following from no
apparent external cause receives instant light from the relative
fertility of the fitter and unfitter elements combined with what we
now know of the laws of inheritance.”
[82]
—Peaêson , 1904.
(4) To the question, What were the causes of the fall of Rome?
Mr. Balfour replies, “I feel disposed to answer, Decadence.”
[83]
—
Balfouê , 1908.
The lecture of which the previous chapter is the written form was
prepared and delivered before I had an opportunity of seeing Mr. A.
J. Balfour's lecture on “Decadence” delivered a few days before.
That has since been printed, and is well worthy of our attention. In
Mr. Balfour we have a representative political thinker, an
experimental statesman and, furthermore, a former President of the
British Association, deeply interested in, and favourably disposed
towards, scientific enquiry and the scientific method. Further, this
lecture has been widely noticed, though all the criticisms I have seen
seem to me to miss the point. No apology, then, is necessary for a
special discussion of this most suggestive lecture in direct relation
with the foregoing theory of its subject.
Political and national decadence is Mr. Balfour's theme, and we note
first that here is a contemporary thinker, not unread in recent
biology, including the work of Weismann, who is prepared to make
use of the idea that societies are inherently mortal, as individuals
are. One wonders when we shall be rid of this pernicious instance of
the argument from analogy, which is already much more than two
thousand years old.
Next it may be noticed that, though Mr. Balfour has deliberately
discussed the idea of natural selection, he has been led wholly
astray from its true relation to the question under discussion by
reason of falling into the common error which Sir E. Ray Lankester
has recently exposed, as Huxley did several decades ago. Mr. Balfour
conceives natural selection to issue from the struggle for existence
between species or societies. It has already been pointed out that

59. the all-important natural selection is not between species or societies
but within them. The struggle for existence is fought out mainly
between the immature individuals of any species or society. Its issue
determines the survivors for parenthood and the future. Mr. Balfour
must have read Professor Ray Lankester's recent Romanes Lecture in
which all this is so clearly shown, but he has unfortunately retained
the popular conception of natural selection as acting between
species or societies, and has in consequence failed, I will not say to
find, but even to discuss in any adequate measure, the theory of
racial and national decadence, defined in the preceding chapter. He
merely discusses “competition between groups of communities,” and
rightly finds it inadequate to account for the great tragedies of
history.
There follows a passage which may be heartily assented to, on the
very grounds on which the entire lecture may be welcomed, namely,
that it suggests the inadequacy of the common explanations of
national decadence advanced by historians. Says Mr. Balfour:—
“It is in vain that historians enumerate the public
calamities which preceded, and no doubt contributed to,
the final catastrophe. Civil dissensions, military disasters,
pestilences, famines, tyrants, tax-gatherers, growing
burdens, and waning wealth—the gloomy catalogue is
unrolled before our eyes, yet somehow it does not in all
cases wholly satisfy us: we feel that some of these
diseases are of a kind which a vigorous body politic
should easily be able to survive, that others are
secondary symptoms of some obscurer malady, and that
in neither case do they supply us with the full explanation
of which we are in search.”
One must heartily thank the author for the abundant demonstration
which follows, well warranting our feeling that these explanations do
not suffice—nor yet, in the case of Rome, diminution of population,
nor the “brutalities of the gladiatorial shows,” nor “the gratuitous
distribution of bread to the urban mobs,” nor yet slavery, lately

60. declared, by Mr. W. R. Paterson, in his Nemesis of Nations, to be the
cause of the fall of empires. As Mr. Balfour says, “Who can believe
that this immemorial custom could, in its decline, destroy the
civilisation which, in its vigour, it had helped to create?” It would
have been more important, perhaps, to consider, as Mr. Balfour does
not, the latest view, advanced by Professor Ronald Ross, that the
incursion of malaria may have had something to do with the fall of
Rome.
Mr. Balfour's theory—decadence the cause of decadence.—
Mr. Balfour then falls back upon “decadence "as the explanation, and
to the critic of this elegant hypothesis that decadence is due to
decadence, replies that it is something to recognise the possibility of
"subtle changes in the social tissues of old communities.” One
regrets all the more that he should not have considered anti-eugenic
practices as possibly accounting for these subtle changes. One must,
however, quote the excellent passage in which Mr. Balfour supports
his use of the word decadence, though one utterly disagrees with
the suggestion that the term “old age” might be its equivalent. He
says: “The facile generalisations with which we so often season the
study of dry historic fact; the habits of political discussion which
induce us to catalogue for purposes of debate the outward signs
that distinguish (as we are prone to think) the standing from the
falling state, hide the obscurer, but more potent, forces which
silently prepare the fate of empires.”
We may note with interest (and surely with surprise when we
consider Japan and Spain and the China of to-morrow), Mr. Balfour's
rejection of the doctrine that “arrested progress, and even
decadence, may be but the prelude to a new period of vigorous
growth. So that even those races or nations which seem frozen into
eternal immobility may base upon experience their hopes of an
awakening spring.” It is, I fancy, Mr. Balfour's fondness for the
Platonic idea of senility in the race as in the individual, that leads
him to question what can surely be no longer denied. Thus a little
later we find him saying, “If civilisations wear out, and races become

61. effete, why should we expect to progress indefinitely, why for us
alone is the doom of man to be reversed?”
Nowhere in this lecture is there any recognition of what, I confess,
seems to me to be an obvious and necessary truth, the distinction
between the two kinds of progress—racial progress due to the
choice of the best for parenthood, and acquired or traditional
progress. It may be suggested that no one can usefully discuss
decadence or progress until he has seen and perceived this
absolutely cardinal distinction, suggested in my Royal Institution
lectures in February, 1907, as one of the great lessons taught by the
study of biology to the student of progress.
Mr. Balfour does indeed avoid all those false solutions which depend
upon a Lamarckian belief in the transmission of acquired characters.
This, however, instead of leading him to insist upon the Darwinian
contribution to the study of decadence—the idea of selection—
causes him to regard the racial question as unimportant. He notes
one or two of the fashions in which the quality of a race may be
modified, thus influencing national character, and then dismisses this
question (wherein, as I cannot doubt, everything material lies) with
the remark, “But such changes are not likely, I suppose, to be
considerable, except perhaps those due to the mixture of races—and
that only in new countries.”—Reaching page 45, the reader finds
himself confident that now at length the writer has put his finger on
the crux of the problem. Yet that is how he dismisses it; adding,
indeed, to make it quite clear, the following words: “The flexible
element in any society, that which is susceptible of progress or
decadence, must therefore be looked for rather in the physical and
psychical conditions affecting the life of its component units, than in
their inherited constitution.”
Not a word as to cessation of selection! This omission, which is,
indeed, the omission of the fact of decadence, mainly depends, one
fancies, upon that erroneous conception of natural selection as
acting between species and societies rather than within them, which
for so many decades the biologist has been at pains to correct. One

62. would indeed have thought that, for a scholar and student like Mr.
Balfour, Wordsworth's great sonnet would have sufficed to set up a
train of thought which, fusing with ordinary biological principles,
would have led him to what I believe to be the truth. Let us for a
moment turn to its consideration:—
“When I have borne in memory what has tamed
Great Nations, how ennobling thoughts depart
When men change swords for ledgers....”
Should not this be enough to suggest to us the real meaning of the
consequence which has followed when men changed swords for
ledgers, and which even those who hate war as a vile blasphemy
against life must recognise? It is that, as we have seen, when a
nation is making its way there is selection of the fittest by the stern
arbitrament of war, in which the battle is to the individually strong
and fleet and brave and quick-witted. Later, “when men change
swords for ledgers,” selection ceases; and that is why nothing fails
like success. Yet later still, as France should know, selection by war
must take the form of reversed selection, the flower of a nation's
youth being immolated on the battle-field, whilst its future is
determined by the weak and small and diseased, whom the
recruiting sergeant rejects. “You are not good enough to be a
soldier,” he says; “stay at home and be a father.” That was what
Napoleon did for France.
But to return—for the relations of war to eugenics would really
demand a volume—it may be noted that, though rejecting the
Lamarckian theory—the theory on which nothing should succeed like
success—Mr. Balfour nowhere emphasises the amazing paradox of
history that nothing fails like success. If we consider this fact with
the idea of natural selection in our minds (not between societies but
within them), we cannot fail to perceive that success involves failure
because it involves failure of selection, and therefore indiscriminate
survival; or indeed, survival of the worst.

63. Politics and domestics.—It is, perhaps, a noteworthy comment
upon what may be called the political state of mind, that even when
the idea of natural selection has entered it, the bias is towards
associating it with international and not with intra-national or
domestic politics. The time will come, however, when the politician—
or shall we say the statesman?—realises that it is the domestic
policy, it is the internal struggle for survival within a society, that
conditions and fore-ordains all international politics. The history of
nations is determined not on the battlefield but in the nursery, and
the battalions which give lasting victory are battalions of babies. The
politics of the future will be domestics.
Having rejected so many solutions of his problem, and having
ignored the solution which is advanced in this volume, Mr. Balfour is
reduced to such desperate resorts as phrases like this: “The point at
which the energy of advance is exhausted”—a mere meaningless
phrase; and even such an explanation as that through “mere
weariness of spirit the community resigns itself to ... stagnation.”
One is inclined to throw up one's hands and ask—Do you, then, who
deny the Lamarckian theory, suppose that the fresh children come
into the world with this “mere weariness of spirit”? Has this been
observed in children? Is there anything conceivable that has been
less observed in children, in all times and all places? And if that be
so, what kind of explanation of decadence is this?
Science and industry.—Lastly, in a series of fine passages, Mr.
Balfour offers us some hope in the help of science. Politics, says our
ex-Premier, too often means “the barren exchange of one set of
tyrants or jobbers, for another”: a Daniel come to judgment. We
owe the modern spirit and modern progress, he tells us, neither to
politicians nor to political institutions, nor to theologians nor to
philosophers, but to science, which, he well says, “is the great
instrument of social change, all the greater because its object is not
change but knowledge; and its silent appropriation of this dominant
function, amid the din of political and religious strife, is the most
vital of all the revolutions which have marked the development of
modern civilisation.”

64. And our cause of hope is “a social force, new in magnitude if not in
kind ... the modern alliance between pure science and industry.” To
this I answer a thousand times yes, but I must define the kind of
industry. It is the culture of the racial life which is the vital industry
of any nation, and which Mr. Balfour has not even distantly alluded
to. I agree that our hope for the future is to be found in science:
that, as has been said already, perchance our acquired or traditional
progress in knowledge has now reached the point at which we have
sufficient to reveal to us the necessity of racial progress and the
means by which that may be effected.
“Science and industry,”—yes, indeed! But the industry is to be the
making not of machines but men. The products of progress are not
mechanisms but men, and one may now ask, What is the industry
whose products can be named in the same breath with the men and
women who shall yet be produced by the supreme industry of race-
culture?
CHAPTER XVII
THE PROMISE OF RACE-CULTURE
“The best is yet to be.”
In its form of what we have called negative eugenics, the practice of
our principle would assuredly reduce to an incalculable extent the
amount of human defect, mental and physical, which each
generation now exhibits. This alone, as has been said, would be far
more than sufficient to justify us. A world without hereditary disease
of mind and body, and its grave social consequences, would alone
warrant the hint of Ruskin that posterity may some day look back
upon us with “incredulous disdain.” Yet, assuming that this could be

65. accomplished, as it will be accomplished, what more is to be hoped
for? Must race-culture cease merely when it has raised the average
of the community by reducing to a minimum the proportion of those
who are thus grossly defective in mind or body? Such disease apart,
are we to be content, must we be content, with the present level of
mediocrity in respect of intelligence and temper and moral
sentiment? Can we anticipate a London in which the present ratio of
musical comedy to great opera will be reversed, in which the works
of Mr. George Meredith will sell in hundreds of thousands, whilst
some of our popular novelists will have to find other means of
earning a living? Can we make for a critical democracy which no
political party can fool, and which will choose its best to govern it?
Yet more, can we undertake, now or hereafter, to provide every
generation with its own Shakespeare and Beethoven and Tintoretto
and Newton? What, in a word, is the promise of positive eugenics? It
is to this aspect of the question that Mr. Galton has mainly directed
himself. Indeed he was led to formulate the principles and ideals of
the new science by his study of hereditary genius some four decades
ago. Let us now attempt to answer some of these questions.
The production of genius.—And first as to the production of
genius. It is this, perhaps, that has been the main butt of the jesters
who pass for philosophers with some of us to-day. It may be said at
once that neither Mr. Galton nor any other responsible person has
ever asserted that we can produce genius at will. The difficulties in
the way of such a project—at present—are almost innumerable. One
or two may be cited.
In the first place, there is the cardinal—but by no means universal—
difficulty that the genius is too commonly so occupied with the
development and expansion of his own individuality that he has little
time or energy for the purposes of the race. This, of course, is an
example of Spencer's great generalisation as to the antagonism or
inverse ratio between individuation and genesis.
Again, there is the generalisation of heredity formulated by Mr.
Galton, and named by him the law of regression towards mediocrity.

66. It asserts that the children of those who are above or below the
mean of a race, tend to return towards that mean. The children of
the born criminal will be probably somewhat less criminal in
tendency than he, though more criminal than the average citizen.
The children of the man of genius, if he has any, will probably be
nearer mediocrity than he, though on the average possessing
greater talent than the average citizen. It is thus not in the nature of
sheer genius to reproduce on its own level. It is only the critics who
are wholly ignorant of the elementary facts of heredity that attribute
to the eugenist an expectation of which no one knows the absurdity
so well as he does.
On the other hand, it is impossible to question that the hereditary
transmission of genius or great talent does occur. One may cite at
random such cases as that of the Bach family, Thomas and Matthew
Arnold, James and John Stuart Mill: and the reader who is inclined to
believe that there is no law or likelihood in this matter, must certainly
make himself acquainted with Mr. Galton's Hereditary Genius, and
with such a paper as that which he printed in Sociological Papers,
1904, furnishing an “index to achievements of near kinsfolk of some
of the Fellows of the Royal Society.” There is, of course, the obvious
fallacy involved in the possibility that not heredity but environment
was really responsible for many of these cases. It must have been a
great thing to have such a father as James Mill. But it would be
equally idle to imagine that the evidence can be dismissed with this
criticism. A Matthew Arnold, a John Stuart Mill, could not be
manufactured out of any chance material by an ideal education
continued for a thousand years.
The transmission of genius.—One single instance of the
transmission of genius or great talent in a family may be cited. We
shall take the family which produced Charles Darwin, the discoverer
of the fundamental principle of eugenics, and his first cousin, Francis
Galton. Darwin's grandfather was Erasmus Darwin, physician, poet
and philosopher, and independent expounder of the doctrine of
organic evolution. Darwin's father was a distinguished physician,
described by his son as “the wisest man I ever knew.” Darwin's

67. maternal grandfather was Josiah Wedgwood, the famous founder of
the pottery works. Amongst his first cousins is Mr. Francis Galton. He
has five living sons, each a man of great distinction, including Mr.
Francis Darwin and Sir George Darwin, both of them original
thinkers, honoured by the presidency of the British Association. No
one will put such a case as this down to pure chance or to the
influence of environment alone. This is evidently, like many others, a
greatly distinguished stock. The worth of such families to a nation is
wholly beyond any one's powers of estimation. What if Erasmus
Darwin had never married!
No student of human heredity can doubt that, however limited our
immediate hopes, facts such as those alluded to furnish promise of
great things for the future. But let us turn now from genius to what
we usually call talent.
The production of talent.—There can be no question that
amongst the promises of race-culture is the possibility of breeding
such things as talent and the mental energy upon which talent so
largely depends. In his Inquiries into Human Faculty, Mr. Galton
shows the remarkable extent to which energy or the capacity for
labour underlies intellectual achievement. He says, of energy—
“It is consistent with all the robust virtues, and makes a
large practice of them possible. It is the measure of
fulness of life; the more energy the more abundance of
it; no energy at all is death; idiots are feeble and listless.
In the enquiries I made on the antecedents of men of
science no points came out more strongly than that the
leaders of scientific thought were generally gifted with
remarkable energy, and that they had inherited the gift of
it from their parents and grandparents. I have since
found the same to be the case in other careers.... It may
be objected that if the race were too healthy and
energetic there would be insufficient call for the exercise
of the pitying and self-denying virtues, and the character
of men would grow harder in consequence. But it does

68. not seem reasonable to preserve sickly breeds for the
sole purpose of tending them, as the breed of foxes is
preserved solely for sport and its attendant advantages.
There is little fear that misery will ever cease from the
land, or that the compassionate will fail to find objects for
their compassion; but at present the supply vastly
exceeds the demand: the land is over-stocked and over-
burdened with the listless and the incapable. In any
scheme of eugenics, energy is the most important quality
to favour; it is, as we have seen, the basis of living
action, and it is eminently transmissible by descent.”
Need it be pointed out that any political system which ceases to
favour or actively disfavours energy, making it as profitable to be
lazy as to be active, is anti-eugenic, and must inevitably lead to
disaster? That, however, by the way. Our present point is that
eugenics can reasonably promise, when its principles are recognised,
to multiply the human
[84]
and diminish the vegetable type in the
community. In so doing, it will greatly further the production of
talent, and therefore of that traditional or acquired progress which
men of talent and genius create. Such a result will also further,
though indirectly, the production of genius itself. For, as Mr. Galton
points out, “men of an order of ability which is now very rare, would
become more frequent, because the level out of which they rose
would itself have risen.”
This is by no means the only fashion in which an effective and
practicable race-culture would serve genius, and I shall not be
blamed for considering this matter further by any reader who
realises, however faintly, what the man of genius is worth to the
world. If it were shown possible to establish such social conditions
that genius could never flower in them, we should realise that their
establishment would mean the putting of an end to progress and the
blasting of all the highest hopes of the highest of all ages.
The immediate need of this age, as of all ages, is perhaps not so
much the birth of babies capable of developing into men and women

69. of genius, as the full exploitation of the possibilities of genius with
which, as I fancy, every generation on the average is about as well
endowed as any other. There is, of course, the popular doctrine that
there are no mute inglorious Miltons, that “genius will out,” and that
therefore if it does not appear, it is not there to appear. In
expressing the compelling power of genius in many cases, this
doctrine is not without truth. Yet history abounds in instances where
genius has been destroyed by environment—and we can only guess
how many more instances there are of which history has no record.
To take the single case of musical genius, it is a lamentable thought
that there may be those now living whose natural endowments, in a
favourable environment, would have enabled them to write
symphonies fit to place beside Beethoven's, but whom some
environmental factors—conventional, economic, educational, or what
not—have silenced; or worse, have persuaded to write such sterile
nullities as need not here be instanced. There is surely no waste in
all this wasteful world so lamentable as this waste of genius.
If, then, anyone could devise for us a means by which the genius,
potentially existing at any time, were realised, he would have
performed in effect a service equivalent to that of which eugenics
repudiates the present possibility—the actual creation of genius. But
if we consider what the conditions are which cause the waste of
genius, we realise at once that they mainly inhere in the level of the
human environment of the priceless potentiality in question. As we
noted elsewhere, in an age like that of Pericles genius springs up on
all hands. It is encouraged and welcomed because the average level
of the human environment in which it finds itself is so high. But if
eugenics can raise the average level of intelligence, in so doing not
merely does it render more likely, as Mr. Galton points out, the
production of men of the highest ability, but it provides those
conditions in which men of genius, now swamped, can swim. We
could not undertake to produce a Shakespeare, but we might
reasonably hope to produce a generation which would not damage
or destroy its Shakespeares. And even if men of genius still found it
necessary, as men of genius have found it necessary, to “play to the

70. gallery,” they would play, as Mr. Galton says of the demagogue in a
eugenic age, “to a more sensible gallery than at present.”
Darwin somewhere points out that it is not the scientific, but the
unscientific man who denies future possibilities. Thus though an
advocate of eugenics may be applauded for his judgment if he
declares that the creation of genius will for ever be impossible, yet I
should not care to assert that the ultimate limitations of eugenics
can thus be defined. We have yet to hear the last of Mendelism.
Eugenics and unemployment.—Let us look now at another
aspect of the promise of race-culture. When the time comes that
quality rather than quantity is the ideal of those who concern
themselves with the population question, it is quite evident that not
a few of the social problems which we now find utterly insoluble will
disappear. In this brief outline, we can only allude to one or two
points. Take, for instance, the question of unemployment. We know
that some by no means small proportion of the unemployed were
really destined to be unemployable from the first, as for instance by
reason of hereditary disease. It were better for them and for us had
they never been born. Many more of the unemployed have been
made unemployable by the influence of over-crowding, to which
they were subjected in their years of development. Is there, can
there be, any real and permanent remedy for over-crowding, but the
erection of parenthood into an act of personal and provident
responsibility?
Eugenics and woman.—Take, again, the woman question. No one
will deny that in many of its gravest forms, especially in its economic
form, and the question of the employment of women, wisely or
horribly, this depends (to a degree which few, I think, realise) upon
the fact that there are now, for instance, 1,300,000 women in excess
in this country. Is it then proposed, the reader will say, by means of
race-culture to exterminate the superfluous woman? Indeed, no. But
is the reader aware that Nature is not responsible for the existence
of the superfluous woman? There are more boys than girls born in
the ratio of about 103 or 104 to 100: and Nature means them all to

71. live, boys and girls alike. If they did so live, we should have merely
the problem of the superfluous man, which would not be an
economic problem at all. But we destroy hosts of all the children that
are born, and since male organisms are in general less resistant than
female organisms, we destroy a disproportionate number of boys, so
that the natural balance of the sexes is inverted. Unlike ancient
societies, we largely practise male infanticide. Can the reader believe
that there is any permanent and final means of arresting this
wastage of child-life, with its singular and far-reaching
consequences,—other than the elevation of parenthood, on the
principles which race-culture enjoins, even wholly apart from the
question of the selection of parents? We shall not succeed in keeping
all the children alive (with a trivial number of exceptions), thereby
abolishing the superfluous woman by keeping alive the boy who
should have grown up to be her partner, until we greatly reduce the
birth-rate; as it must and will be reduced when the ideal of race-
culture is realised, and no child comes into the world that is not
already loved and desired in anticipation.
Eugenics and cruelty to children.—This ideal, also, offers us in
its realisation the only complete remedy for the present ghastly
cruelty under which so many children suffer even in Great Britain,
even in the twentieth century. Is the reader aware that the National
Society for the Prevention of Cruelty to Children enquired into the ill-
treatment or cruel neglect of 115,000 children in the year beginning
April 1st, 1906? It has been reasonably and carefully estimated that
“over half a million children are involved in the total of the wastage
of child-life and the torture and neglect of child-life in a single year.”
Surely Mr. G. R. Sims, to whom I would offer a hearty tribute for his
recent services to childhood, is justified in saying, “Against the guilt
of race-suicide our men of science are everywhere preaching their
sermons to-day. It is against the guilt of race-murder that the cry of
the children should ring through the land.” As regards race suicide
and the men of science, I am not so sure as to the assertion. But the
truth of the second sentence quoted is as indisputable as it is
horrible.

72. Now no legislation conceivable will wholly cure this evil nor avert its
consequences. At bottom it depends upon human nature, and you
can cure it only by curing the defect of human nature. This, in
general, is of course beyond the immediate powers of man, but
evidently we should gain the same end if only we could confine the
advent of children to those parents who desired them—that is to say,
those in whom human nature displayed the first, if not indeed
almost the only, requisite for the happiness of childhood. To this
most beneficent and wholly moral end we shall come,
notwithstanding the blind and pitiable guidance of most of our
accredited moral teachers to-day. By no other means than the
realisation of the ideal defined, that every new baby shall be loved
and desired in anticipation—an ideal which is perfectly practicable—
can the black stain of child murder and child torture and child
neglect be removed from our civilisation.
Ruskin and race-culture.—The name of Ruskin, perhaps, would
not occur to the reader as likely to afford support to the fair hopes of
the eugenist. Consider then, these words from Time and Tide:—

73. “You leave your marriages to be settled by supply and
demand, instead of wholesome law. And thus, among
your youths and maidens, the improvident, incontinent,
selfish, and foolish ones marry, whether you will or not;
and beget families of children necessarily inheritors in a
great degree of these parental dispositions; and for
whom, supposing they had the best dispositions in the
world, you have thus provided, by way of educators, the
foolishest fathers and mothers you could find; (the only
rational sentence in their letters, usually, is the invariable
one, in which they declare themselves ‘incapable of
providing for their children's education’). On the other
hand, whosoever is wise, patient, unselfish, and pure
among your youth, you keep maid or bachelor; wasting
their best days of natural life in painful sacrifice,
forbidding them their best help and best reward, and
carefully excluding their prudence and tenderness from
any offices of parental duty. Is not this a beatific and
beautifully sagacious system for a Celestial Empire, such
as that of these British Isles?”
Apart from the point as to wholesome law rather than the education
of opinion as the eugenic means, the foregoing passage must win
the assent and respect of every eugenist. It indicates the promise of
race-culture as it appeared to John Ruskin. The passage has been
quoted in full not for the benefit of the ordinary thoughtful reader
but for that of the professional literary man who, in this remarkable
age, so far as I can judge, reads nothing but what he writes, and
thus qualifies himself for dismissing Spencer or Darwin or Galton in
any casual phrase—meanwhile condemning Ruskin, whom he
probably professes to adore.
Race-culture and human variety.—Now let us turn to another
question. Let it be asserted most emphatically that, if there is
anything in the world which eugenics or race-culture does not
promise or desire, it is the production of a uniform type of man. This

74. delusion, for which there has never been any warrant at all,
possesses many of the critics of eugenics, and they have made
pretty play with it, just as they do with their other delusions. Let us
note one or two facts which bear upon this most undesirable ideal.
In the first place, it is unattainable because of the existence of what
we call variation. No apparatus conceivable would suffice to
eliminate from every generation those who varied from the accepted
type.
In the second place, this uniformity is supremely undesirable from
the purely evolutionary point of view, because its attainment would
mean the arrest of all progress. All organic evolution, as we know,
depends upon the struggle between creatures possessing variations
and the consequent selection of those variations which constitute
their possessors best adapted or fitted to the particular environment.
If there is no variation there can be no evolution. To aim at the
suppression of variation, therefore, on supposed eugenic grounds
(which would be involved in aiming at any uniform type of mankind)
would be to aim at destroying the necessary condition of all racial
progress. The mere fact that the critics of race-culture attribute to
evolutionists, of all people, the desire to suppress variation, is a
pathognomic symptom of their critical quality.
And, of course, quite independently of the evolutionary function of
variation—though this is cardinal and must never be forgotten by the
politician of any school, since what we call individuality is variation
on the human plane—the value of variation in ordinary life is wholly
incalculable. It is not merely that, as Mr. Galton says, “There are a
vast number of conflicting ideals, of alternative characters, of
incompatible civilisations; but they are wanted to give fulness and
interest to life. Society would be very dull if every man resembled
the highly estimable Marcus Aurelius or Adam Bede.” The question is
not merely as to the interest of life. Much more important is the fact
that it takes all sorts to make a world. What is the development of
society but the result of the psychological division of labour in the
social organism? And how could such division of labour be carried

75. out if we had not various types of labourers? What would be the
good of science if there were no poetry or music to live for? How
would poetry and music help us if we had not men of science to
protect our shores from plague?
Obviously the existence of men of most various types is a necessity
for any highly organised society. Even if eugenics were capable—as
it is not—of producing a complete and balanced type, fit up to a
point to turn out a satisfactory poem, a satisfactory symphony or a
satisfactory sofa, the utmost could not be expected of such a man in
any of these directions. In a word, as long as their activities are not
anti-social, men cannot be of too various types. We require mystic
and mathematician, poet and pathologist. Only, we want good
specimens of each. “The aim of eugenics,” says Mr. Galton, “is to
represent each class or sect by its best specimens; that done, to
leave them to work out their common civilisation in their own way....
Special aptitudes would be assessed highly by those who possessed
them, as the artistic faculties by artists, fearlessness of enquiry and
veracity by scientists, religious absorption by mystics, and so on.
There would be self-sacrificers, self-tormentors, and other
exceptional idealists.” But at least it is better to have good rather
than bad specimens of any kind, whatever that kind may be. Mr.
Galton thinks that all except cranks would agree as to including
health, energy, ability, manliness and courteous disposition amongst
qualities uniformly desirable—alike in poet and pathologist. We
should desire also uniformity as to the absence of the anti-social
proclivities of the born criminal. So much uniformity being granted,
let us have with it the utmost conceivable variety,—more, indeed,
than most of us can conceive.
This point, of course, is cardinal from the point of view of practice.
No progress could be made with eugenics, it would be impossible
even to form a Eugenics Education Society, if each of us were to
regard the particular type he belongs to as the ideal, and were to
seek merely to obtain the best specimens of that type. The doctrine
that it takes all sorts to make a world—a doctrine very hard for
youth to learn, yet unconsciously learnt by all who are capable of

76. learning at all—must be regarded as a cardinal truth for the
eugenist. But he wisely seeks good specimens rather than bad.
Poets certainly, but not poetasters; jesters certainly, but not clever
fools, who stand Truth on her head and then make street-boy
gestures at her.
Time and its treasure.—Taking the modern estimates of the
physicists, we are assured that the total period of past human
existence is very brief compared with what may reasonably be
predicted. Granted, then, practically unlimited time, what inherent
limits are there to the upward development of man as a moral and
intellectual being? Shall we answer this question by a study of the
nature of matter? Plainly not. Shall we answer it by a study of the
nature of mind? Surely not, for the study of existing mind cannot
inform us as to what mind might be. One source of guidance alone
we have, and this is the amazing contrast which exists between the
mind of man at its highest, and mind in its humblest animal forms:
or shall we say even between the highest and lowest manifestations
of mind within the human species? The measureless height of the
ascent thus indicated offers us no warrant for the conclusion that, as
we stand on the heights of our life, our “glimpse of a height that is
higher” is only an hallucination. On the contrary.
There is no warrant whatever for supposing that the forces which
have brought us thus far are yet exhausted: they have their origin in
the inexhaustible. Who, gazing on the earth of a hundred million
years ago, could have predicted life—could have recognised, in the
forces then at work and the matter in which they were displayed,
the promise and potency of all terrestrial life? Who, contemplating
life at a much later stage, even later mammalian, could have seen in
the simian the prophecy of man? Who, examining the earliest
nervous ganglia, could have foreseen the human cerebrum? The fact
that we can imagine nothing higher than ourselves, that we make
even our gods in our own image, offers no warrant for supposing
that nothing higher will ever be, What ape could have predicted
man, what reptile the bird, what amœba the bee? “There are many

77. events in the womb of time which will be delivered,” and the fairest
of her sons and daughters are yet to be.
But even grant, for the sake of the argument, that the intelligence of
a Newton, the musical faculty of a Bach, the moral nature of any
good mother anywhere, represent the utmost limits of which the
evolution of the psychical is capable. There is every reason to deny
this, but let us for the moment assume it true. There still remains
the thought of Wordsworth, “What one is, why may not millions
be?”—a thought to which Spencer has also given utterance. What is
shown possible for human nature here and there, he says, is
conceivable for human nature at large. It is possible for a human
being, whilst still remaining human, to be a Shakespeare or a St.
Francis: these things are thus demonstrably within the possibilities of
human nature. It is therefore at the least conceivable that, in the
course of almost infinite time (even assuming, say, that intelligence
must ever be limited, as even Newton's intelligence was limited),
some such capacities as his may be common property amongst men
of the scientific type; and so with other types. We may answer
Wordsworth that there is no bar thrown by Nature in the way of
such a hope.
What is possible?—This, of course, is speculation and of no
immediate value. I would merely remind the reader that the doctrine
of optimism, as regards the future of mankind, which the principles
of race-culture assume and which they desire to justify, was
definitely shared by the great pioneers to whom we owe our
understanding of those principles. Notwithstanding grave nervous
disorder, such as makes pessimists of most men, both Darwin and
Spencer were compelled by their study of Nature to this rational
optimism as regards man's future. The doctrine of organic evolution,
and of the age-long ascent of man through the selection of the
fittest (who have, on the whole, been the best) for parenthood, is
one not of despair but of hope. Exactly half a century ago it struck
horror into the minds of our predecessors. Man, then, is only an
erected ape, they thought—as if any historical doctrine, however
true, could shorten the dizzy distance to which man has climbed

78. since he was simian: and man being an ape, they thought his high
dreams palpably vain. But the measure of the accomplished hints at
the measure of the possible, and the value of the historical facts lies
not in themselves, all facts as such being as dead as are the
individual atoms of the living body, but in the principles which grow
out of them. It is of no importance as such that man has simian
ancestors; it is of immeasurable importance that he should learn by
what processes he has become human, and by what, indeed, they
became simian—which would have been a proud adjective for its
own day. The principles of organic progress matter for us because
they are the principles of race-culture, the only sure means of
human progress. Our looking backwards does not turn us into pillars
of salt, but teaches us that the best is yet to be, and how alone it is
to be attained.
Elsewhere the optimistic argument of Wordsworth is quoted. Hear
also John Ruskin:—
“There is as yet no ascertained limit to the nobleness of
person and mind which the human creature may attain,
by persevering observance of the laws of God respecting
its birth and training.”
[85]
and Herbert Spencer:—
“What now characterises the exceptionally high may be
expected eventually to characterise all. For that which the
best human nature is capable of, is within the reach of
human nature at large.”
[86]
and Francis Galton:—
“There is nothing either in the history of domestic animals
or in that of evolution to make us doubt that a race of
sane men may be formed, who shall be as much superior,
mentally and morally, to the modern European, as the
modern European is to the lowest of the Negro races.

79. “It is earnestly to be hoped that enquiries will be
increasingly directed into historical facts, with the view of
estimating the possible effects of reasonable political
action in the future, in gradually raising the present
miserably low standard of the human race to one in
which the Utopias in the dreamland of philanthropists
may become practical possibilities.”
[87]
Conclusion—Eugenics and Religion.—In an early chapter it was
attempted to show that eugenics is not merely moral, but is of the
very heart of morality. We saw that it involves taking no life, that,
rather, it desires to make philanthropy more philanthropic, that, at
any rate so far as this eugenist is concerned, it recognises and bows
to the supreme law of love: and claims to serve that law, and the
ideal of social morality, which is the making of human worth.
Eugenics may or may not be practicable, it may or may not be based
upon natural truth, but it is assuredly moral: though I, for one,
would proclaim eternal war between this real morality and the
damnable sham which approves the unbridled transmission of the
most hideous diseases, rotting body and soul, in the interests of
good.
And if religion, whatever its origin and the more questionable
chapters in its past, be now “morality touched with emotion,” I claim
that eugenics is religious, is and will ever be a religion. Elsewhere
[88]
I have attempted to show that religion has survived and will survive
because of its survival-value—its services to the life of the societies
wherein it flourishes. The religion of the future, it was sought to
argue, will be that which “best serves Nature's unswerving desire—
fulness of life.” The Founder of the Christian religion said, “I am
come that ye might have life, and that ye might have it more
abundantly.” It is higher and more abundant life that is the eugenic
ideal. Progress I define as the emergence and increasing dominance
of mind. Of progress, thus conceived, man is the highest fruit
hitherto. He is also its appointed agent, and eugenics is his
instrument.

80. To this end he must use all the powers which have blossomed in him
from the dust. He must claim Art: and indeed in Wagner's great
music-drama, at the moment when the prophetic Brünnhilde tells
Sieglinde who has just lost her mate that she, the expectant mother,
may look for the resurrection of the dead and the life of the world to
come in the child Siegfried; and when the heroic theme is
pronounced for the first time and followed by that which signifies
redemption by love—then, I think, the eugenist may thrill not merely
to the music, or to the humanity of the story, but to the spiritual and
scientific truth which it symbolises.
If the struggle towards individual perfection be religious, so,
assuredly, is the struggle, less egoistic, indeed, towards racial
perfection. If the historic meaning and purport of religion are as I
conceive them, and if its future evolution may thence be inferred,
there can be no doubt in the prophecy that in ages to come those
high aspirations and spiritual visions which astronomy has dishoused
from amongst the stars, and which, at their best, were ever selfish,
will find a place on this human earth of ours. If we have transferred
our hopes from heaven to earth and from ourselves to our children,
they are not less religious. And they that shall be of us shall build
the old waste places; for we shall raise up the foundations of many
generations:
“We feed the high tradition of the world,
And leave our spirits in our children's breasts.”

81. APPENDIX
CONCERNING BOOKS TO READ
The preceding pages are of course only tentative, preliminary and
introductory. I have merely tried to make a beginning. No better
purpose can be achieved than that the reader should proceed to
study the subject for himself. A few pages may therefore be devoted
to the names of some of the books which will be found useful. This
is in no sense a complete bibliography, nor even a tithe of such a
bibliography. But the reader who makes a beginning with the books
here named, or even with a well-chosen half dozen of them, will
thereafter need no one to tell him that the culture of the human race
on scientific principles will be the supreme science of all the future,
the supreme goal of all statesmen, the object and the final judge of
all legislation.
Where it is thought that useful remarks can be made they will be
made, but neither their presence nor absence nor their length is to
be taken as any index to the writer's opinion of the relative value of
the works in question.
Heredity. (The Progressive Science Series, 1908.) By Professor J. A.
Thomson , M.A.
This is the most recent and most valuable for general purposes of all
books on the subject of heredity. No layman should express opinions
on heredity or eugenics until he has read it, for it is extremely
improbable that they will be valuable. Professor Thomson covers the
whole ground with extreme lucidity and care and impartiality. The
book is readable, nay more, fascinating from end to end, and it is
liberally and usefully illustrated. It is the first general treatise on
heredity which leads consciously, yet as of necessity, towards

82. eugenics as the crown and goal of the whole study, and in this
respect it undoubtedly marks an epoch.
The Methods and Scope of Genetics. (1908.) By W. Bateson, M.A.,
F.R.S.
This is the inaugural lecture, destined, I have little doubt, to become
historic, which was delivered by Professor Bateson on his
appointment to the new Darwin Chair of Biology at Cambridge. It is
purposely included here for very good reasons. The reader who
begins his serious study of heredity with Professor Thomson's work
must be informed that though the author gives an interesting
account of Mendelism, he is not a Mendelian, and neither his
account of Mendelism nor his estimate of it is at all adequate for the
present day. In truth there is the study of heredity before Mendelism
and after, and though eugenics owes its modern origin to the
founder of the school of biometrics, and though among his followers
there are to be found many who decry and oppose the Mendelians,
it is for the eugenist of single purpose to take the truth wherever it
is to be found. It is now idle to deny either the general truth or the
stupendous promise of Mendelism. Many vital phenomena besides
heredity are studied by the statistical method, and are put down by
it to heredity. The Mendelians take seeds of known origin, and plant
them and note the result. They carry out experimental breeding not
only amongst plants but amongst the higher animals, including
mammals who, in all essentials of structure and function, are one
with ourselves. It is not possible, I believe, to over-estimate the
supreme importance of Mendelian enquiry for eugenics. Eugenics is
founded upon heredity, and genetics, which is Professor Bateson's
name for the physiology of heredity and variation, is now working at
the very heart of those natural phenomena upon which eugenics
depends. This lecture of Professor Bateson's is by the far the best
introduction to Mendelism that exists, besides being the most recent
and the most authoritative possible. With the lucidity of the born
teacher (whose faculty, I have no doubt, is a Mendelian unit, not
always inherited by the born observer) the author explains the
essence of Mendelism. The usual expositor has not proceeded far

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